Involvement of human monogenic cardiomyopathy genes in experimental polygenic cardiac hypertrophy
- Prestes, Priscilla, Marques, Francine, Lopez-Campos, Guillermo, Lewandowski, Paul, Delbridge, Lea, Charchar, Fadi, Harrap, Stephen
- Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Lewandowski, Paul , Delbridge, Lea , Charchar, Fadi , Harrap, Stephen
- Date: 2018
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 50, no. 9 (2018), p. 680-687
- Full Text:
- Reviewed:
- Description: Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.
- Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Lewandowski, Paul , Delbridge, Lea , Charchar, Fadi , Harrap, Stephen
- Date: 2018
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 50, no. 9 (2018), p. 680-687
- Full Text:
- Reviewed:
- Description: Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.
May measurement month 2017 : an analysis of blood pressure screening results worldwide
- Beaney, Thomas, Schutte, Aletta, Tomaszewski, Maciej, Ariti, Cono, Burrell, Louise, Castillo, Rafael, Charchar, Fadi, Damasceno, Albertino, Kruger, Ruan, Lackland, Daniel, Nilsson, Peter, Prabhakaran, Dorairaj, Ramirez, Agustin, Schlaich, Markus, Wang, Jiguang, Weber, Michael, Poulter, Neil
- Authors: Beaney, Thomas , Schutte, Aletta , Tomaszewski, Maciej , Ariti, Cono , Burrell, Louise , Castillo, Rafael , Charchar, Fadi , Damasceno, Albertino , Kruger, Ruan , Lackland, Daniel , Nilsson, Peter , Prabhakaran, Dorairaj , Ramirez, Agustin , Schlaich, Markus , Wang, Jiguang , Weber, Michael , Poulter, Neil
- Date: 2018
- Type: Text , Journal article
- Relation: The Lancet Global Health Vol. 6, no. 7 (2018), p. e736-e743
- Full Text:
- Reviewed:
- Description: Background: Increased blood pressure is the biggest contributor to the global burden of disease and mortality. Data suggest that less than half of the population with hypertension is aware of it. May Measurement Month was initiated to raise awareness of the importance of blood pressure and as a pragmatic interim solution to the shortfall in screening programmes. Methods: This cross-sectional survey included volunteer adults (≥18 years) who ideally had not had their blood pressures measured in the past year. Each participant had their blood pressure measured three times and received a a questionnaire about demographic, lifestyle, and environmental factors. The primary objective was to raise awareness of blood pressure, measured by number of countries involved, number of people screened, and number of people who have untreated or inadequately treated hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, or on the basis of receiving antihypertensive medication). Multiple imputation was used to estimate the mean of the second and third blood pressure readings if these were not recorded. Measures of association were analysed using linear mixed models. Findings: Data were collected from 1 201 570 individuals in 80 countries. After imputation, of the 1 128 635 individuals for whom a mean of the second and third readings was available, 393 924 (34·9%) individuals had hypertension. 153 905 (17·3%) of 888 616 individuals who were not receiving antihypertensive treatment were hypertensive, and 105 456 (46·3%) of the 227 721 individuals receiving treatment did not have controlled blood pressure. Significant differences in adjusted blood pressures and hypertension prevalence were apparent between regions. Adjusted blood pressure was higher in association with antihypertensive medication, diabetes, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm than on the left arm, and blood pressure was highest on Saturdays. Interpretation: Inexpensive global screening of blood pressure is achievable using volunteers and convenience sampling. Pending the set-up of systematic surveillance systems worldwide, MMM will be repeated annually to raise awareness of blood pressure. Funding: International Society of Hypertension, Centers for Disease Control and Prevention, Servier Pharmaceutical Co.
- Authors: Beaney, Thomas , Schutte, Aletta , Tomaszewski, Maciej , Ariti, Cono , Burrell, Louise , Castillo, Rafael , Charchar, Fadi , Damasceno, Albertino , Kruger, Ruan , Lackland, Daniel , Nilsson, Peter , Prabhakaran, Dorairaj , Ramirez, Agustin , Schlaich, Markus , Wang, Jiguang , Weber, Michael , Poulter, Neil
- Date: 2018
- Type: Text , Journal article
- Relation: The Lancet Global Health Vol. 6, no. 7 (2018), p. e736-e743
- Full Text:
- Reviewed:
- Description: Background: Increased blood pressure is the biggest contributor to the global burden of disease and mortality. Data suggest that less than half of the population with hypertension is aware of it. May Measurement Month was initiated to raise awareness of the importance of blood pressure and as a pragmatic interim solution to the shortfall in screening programmes. Methods: This cross-sectional survey included volunteer adults (≥18 years) who ideally had not had their blood pressures measured in the past year. Each participant had their blood pressure measured three times and received a a questionnaire about demographic, lifestyle, and environmental factors. The primary objective was to raise awareness of blood pressure, measured by number of countries involved, number of people screened, and number of people who have untreated or inadequately treated hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, or on the basis of receiving antihypertensive medication). Multiple imputation was used to estimate the mean of the second and third blood pressure readings if these were not recorded. Measures of association were analysed using linear mixed models. Findings: Data were collected from 1 201 570 individuals in 80 countries. After imputation, of the 1 128 635 individuals for whom a mean of the second and third readings was available, 393 924 (34·9%) individuals had hypertension. 153 905 (17·3%) of 888 616 individuals who were not receiving antihypertensive treatment were hypertensive, and 105 456 (46·3%) of the 227 721 individuals receiving treatment did not have controlled blood pressure. Significant differences in adjusted blood pressures and hypertension prevalence were apparent between regions. Adjusted blood pressure was higher in association with antihypertensive medication, diabetes, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm than on the left arm, and blood pressure was highest on Saturdays. Interpretation: Inexpensive global screening of blood pressure is achievable using volunteers and convenience sampling. Pending the set-up of systematic surveillance systems worldwide, MMM will be repeated annually to raise awareness of blood pressure. Funding: International Society of Hypertension, Centers for Disease Control and Prevention, Servier Pharmaceutical Co.
Molecular insights into genome-wide association studies of chronic kidney disease-defining traits
- Xu, Xiaoguang, Eales, James, Akbarov, Artur, Guo, Hui, Becker, Lorenz, Talavera, David, Ashraf, Fehzan, Nawaz, Jabran, Pramanik, Sanjeev, Bowes, John, Jiang, Xiao, Dormer, John, Denniff, Matthew, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Prestes, Priscilla, Glyda, Maciej, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Berzuini, Carlo, Woolf, Adrian, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Xu, Xiaoguang , Eales, James , Akbarov, Artur , Guo, Hui , Becker, Lorenz , Talavera, David , Ashraf, Fehzan , Nawaz, Jabran , Pramanik, Sanjeev , Bowes, John , Jiang, Xiao , Dormer, John , Denniff, Matthew , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Prestes, Priscilla , Glyda, Maciej , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Berzuini, Carlo , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2018
- Type: Text , Journal article
- Relation: Nature communications Vol. 9, no. 1 (2018), p. 1-12
- Full Text:
- Reviewed:
- Description: Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
- Authors: Xu, Xiaoguang , Eales, James , Akbarov, Artur , Guo, Hui , Becker, Lorenz , Talavera, David , Ashraf, Fehzan , Nawaz, Jabran , Pramanik, Sanjeev , Bowes, John , Jiang, Xiao , Dormer, John , Denniff, Matthew , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Prestes, Priscilla , Glyda, Maciej , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Berzuini, Carlo , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2018
- Type: Text , Journal article
- Relation: Nature communications Vol. 9, no. 1 (2018), p. 1-12
- Full Text:
- Reviewed:
- Description: Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
A novel Y-specific long non-coding RNA associated with cellular lipid accumulation in HepG2 cells and Atherosclerosis-related genes
- Molina, Elsa, Chew, Guat, Myers, Stephen, Clarence, Elyse, Eales, James, Tomaszewski, Maciej, Charchar, Fadi
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
Experimental and human evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin NGAL ) in the development of cardiac hypertrophy and heart failure
- Marques, Francine, Prestes, Priscilla, Byars, Sean, Ritchie, Scott, Wurtz, Peter, Patel, Sheila, Booth, Scott, Rana, Indrajeetsinh, Minoda, Yosuke, Berzins, Stuart, Curl, Claire, Bell, James, Wai, Bryan, Srivastava, Piyush, Kangas, Antti, Soininen, Pasi, Ruohonen, Saku, Kahonen, Mika, Lehtimaki, Terho, Raitoharju, Emma, Havulinna, Aki, Perola, Markus, Raitakari, Olli, Salomaa, Veikko, Ala-Korpela, Mika, Kettunen, Johannes, McGlynn, Maree, Kelly, Jason, Wlodek, Mary, Lewandowski, Paul, Delbridge, Lea, Burrell, Louise, Inouye, Michael, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Prestes, Priscilla , Byars, Sean , Ritchie, Scott , Wurtz, Peter , Patel, Sheila , Booth, Scott , Rana, Indrajeetsinh , Minoda, Yosuke , Berzins, Stuart , Curl, Claire , Bell, James , Wai, Bryan , Srivastava, Piyush , Kangas, Antti , Soininen, Pasi , Ruohonen, Saku , Kahonen, Mika , Lehtimaki, Terho , Raitoharju, Emma , Havulinna, Aki , Perola, Markus , Raitakari, Olli , Salomaa, Veikko , Ala-Korpela, Mika , Kettunen, Johannes , McGlynn, Maree , Kelly, Jason , Wlodek, Mary , Lewandowski, Paul , Delbridge, Lea , Burrell, Louise , Inouye, Michael , Harrap, Stephen , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 6, no. 6 (2017), p. 1-58
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
- Full Text:
- Reviewed:
- Description: Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
- Authors: Marques, Francine , Prestes, Priscilla , Byars, Sean , Ritchie, Scott , Wurtz, Peter , Patel, Sheila , Booth, Scott , Rana, Indrajeetsinh , Minoda, Yosuke , Berzins, Stuart , Curl, Claire , Bell, James , Wai, Bryan , Srivastava, Piyush , Kangas, Antti , Soininen, Pasi , Ruohonen, Saku , Kahonen, Mika , Lehtimaki, Terho , Raitoharju, Emma , Havulinna, Aki , Perola, Markus , Raitakari, Olli , Salomaa, Veikko , Ala-Korpela, Mika , Kettunen, Johannes , McGlynn, Maree , Kelly, Jason , Wlodek, Mary , Lewandowski, Paul , Delbridge, Lea , Burrell, Louise , Inouye, Michael , Harrap, Stephen , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 6, no. 6 (2017), p. 1-58
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
- Full Text:
- Reviewed:
- Description: Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
MicroRNAs in a hypertrophic heart : From foetal life to adulthood
- Sadiq, Shahzad, Crowley, Tamsyn, Charchar, Fadi, Sanigorski, Andrew, Lewandowski, Paul
- Authors: Sadiq, Shahzad , Crowley, Tamsyn , Charchar, Fadi , Sanigorski, Andrew , Lewandowski, Paul
- Date: 2017
- Type: Text , Journal article
- Relation: Biological Reviews Vol. 92, no. 3 (2017), p. 1314-1331
- Full Text:
- Reviewed:
- Description: The heart is the first organ to form and undergoes adaptive remodelling with age. Ventricular hypertrophy is one such adaptation, which allows the heart to cope with an increase in cardiac demand. This adaptation is necessary as part of natural growth from foetal life to adulthood. It may also occur in response to resistance in blood flow due to various insults on the heart and vessels that accumulate with age. The heart can only compensate to this increase in workload to a certain extent without losing its functional architecture, ultimately resulting in heart failure. Many genes have been implicated in cardiac hypertrophy, however none have been shown conclusively to be responsible for pathological cardiac hypertrophy. MicroRNAs offer an alternative mechanism for cellular regulation by altering gene expression. Since 1993 when the function of a non-coding DNA sequence was first discovered in the model organism Caenorhabditis elegans, many microRNAs have been implicated in having a central role in numerous physiological and pathological cellular processes. The level of control these antisense oligonucleotides offer can often be exploited to manipulate the expression of target genes. Moreover, altered levels of microRNAs can serve as diagnostic biomarkers, with the prospect of diagnosing a disease process as early as during foetal life. Therefore, it is vital to ascertain and investigate the function of microRNAs that are involved in heart development and subsequent ventricular remodelling. Here we present an overview of the complicated network of microRNAs and their target genes that have previously been implicated in cardiogenesis and hypertrophy. It is interesting to note that microRNAs in both of these growth processes can be of possible remedial value to counter a similar disease pathophysiology.
- Authors: Sadiq, Shahzad , Crowley, Tamsyn , Charchar, Fadi , Sanigorski, Andrew , Lewandowski, Paul
- Date: 2017
- Type: Text , Journal article
- Relation: Biological Reviews Vol. 92, no. 3 (2017), p. 1314-1331
- Full Text:
- Reviewed:
- Description: The heart is the first organ to form and undergoes adaptive remodelling with age. Ventricular hypertrophy is one such adaptation, which allows the heart to cope with an increase in cardiac demand. This adaptation is necessary as part of natural growth from foetal life to adulthood. It may also occur in response to resistance in blood flow due to various insults on the heart and vessels that accumulate with age. The heart can only compensate to this increase in workload to a certain extent without losing its functional architecture, ultimately resulting in heart failure. Many genes have been implicated in cardiac hypertrophy, however none have been shown conclusively to be responsible for pathological cardiac hypertrophy. MicroRNAs offer an alternative mechanism for cellular regulation by altering gene expression. Since 1993 when the function of a non-coding DNA sequence was first discovered in the model organism Caenorhabditis elegans, many microRNAs have been implicated in having a central role in numerous physiological and pathological cellular processes. The level of control these antisense oligonucleotides offer can often be exploited to manipulate the expression of target genes. Moreover, altered levels of microRNAs can serve as diagnostic biomarkers, with the prospect of diagnosing a disease process as early as during foetal life. Therefore, it is vital to ascertain and investigate the function of microRNAs that are involved in heart development and subsequent ventricular remodelling. Here we present an overview of the complicated network of microRNAs and their target genes that have previously been implicated in cardiogenesis and hypertrophy. It is interesting to note that microRNAs in both of these growth processes can be of possible remedial value to counter a similar disease pathophysiology.
Telomeres, aging and exercise : Guilty by association?
- Chilton, Warrick, O’Brien, Brendan, Charchar, Fadi
- Authors: Chilton, Warrick , O’Brien, Brendan , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 18, no. 12 (2017), p. 1-32
- Full Text:
- Reviewed:
- Description: Telomeres are repetitive tandem DNA sequences that cap chromosomal ends protecting genomic DNA from enzymatic degradation. Telomeres progressively shorten with cellular replication and are therefore assumed to correlate with biological and chronological age. An expanding body of evidence suggests (i) a predictable inverse association between telomere length, aging and age-related diseases and (ii) a positive association between physical activity and telomere length. Both hypotheses have garnered tremendous research attention and broad consensus; however, the evidence for each proposition is inconsistent and equivocal at best. Telomere length does not meet the basic criteria for an aging biomarker and at least 50% of key studies fail to find associations with physical activity. In this review, we address the evidence in support and refutation of the putative associations between telomere length, aging and physical activity. We finish with a brief review of plausible mechanisms and potential future research directions. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.
- Authors: Chilton, Warrick , O’Brien, Brendan , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 18, no. 12 (2017), p. 1-32
- Full Text:
- Reviewed:
- Description: Telomeres are repetitive tandem DNA sequences that cap chromosomal ends protecting genomic DNA from enzymatic degradation. Telomeres progressively shorten with cellular replication and are therefore assumed to correlate with biological and chronological age. An expanding body of evidence suggests (i) a predictable inverse association between telomere length, aging and age-related diseases and (ii) a positive association between physical activity and telomere length. Both hypotheses have garnered tremendous research attention and broad consensus; however, the evidence for each proposition is inconsistent and equivocal at best. Telomere length does not meet the basic criteria for an aging biomarker and at least 50% of key studies fail to find associations with physical activity. In this review, we address the evidence in support and refutation of the putative associations between telomere length, aging and physical activity. We finish with a brief review of plausible mechanisms and potential future research directions. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.
The y chromosome : A blueprint for men's health?
- Maan, Akhlaq, Eales, James, Akbarov, Artur, Rowland, Joshua, Xu, Xiaoguang, Jobling, Mark, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Maan, Akhlaq , Eales, James , Akbarov, Artur , Rowland, Joshua , Xu, Xiaoguang , Jobling, Mark , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2017
- Type: Text , Journal article , Review
- Relation: European Journal of Human Genetics Vol. 25, no. 11 (2017), p. 1181-1188
- Full Text:
- Reviewed:
- Description: The Y chromosome has long been considered a genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome. © 2017 The Author(s).
- Authors: Maan, Akhlaq , Eales, James , Akbarov, Artur , Rowland, Joshua , Xu, Xiaoguang , Jobling, Mark , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2017
- Type: Text , Journal article , Review
- Relation: European Journal of Human Genetics Vol. 25, no. 11 (2017), p. 1181-1188
- Full Text:
- Reviewed:
- Description: The Y chromosome has long been considered a genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome. © 2017 The Author(s).
Coronary artery disease : Why we should consider the Y chromosome
- Molina, Elsa, Clarence, Elyse, Ahmady, Farah, Chew, Guatsiew, Charchar, Fadi
- Authors: Molina, Elsa , Clarence, Elyse , Ahmady, Farah , Chew, Guatsiew , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Heart Lung and Circulation Vol. 25, no. 8 (Aug 2016), p. 791-801
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality globally. In the last few years our understanding of the genetic and molecular mechanisms that promote CAD in individuals has increased with the advent of the genome era. This complex inflammatory disease has well-defined environmental risk factors. However, in the last 10 years, studies including genome-wide association studies (GWAS) have clearly demonstrated a genetic influence on CAD. Recently, studies on the human Y chromosome have also demonstrated that genetic variation within the male-specific region of the Y chromosome (MSY) could play a part in determining cardiovascular risk in men, confirming the notion that the increased risk for CAD in men cannot be fully explained through common CAD risk factors. Here, we review the literature about the pathophysiology of CAD, its potential causes and environmental risk factors known so far. Furthermore, we review the genetics of CAD, especially the latest discoveries regarding the implication of the Y chromosome, the most underexplored portion of the human genome to date, highlighting methods and difficulties arising in this research field, and discussing the importance of considering the Y chromosome in CAD research.
- Authors: Molina, Elsa , Clarence, Elyse , Ahmady, Farah , Chew, Guatsiew , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Heart Lung and Circulation Vol. 25, no. 8 (Aug 2016), p. 791-801
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality globally. In the last few years our understanding of the genetic and molecular mechanisms that promote CAD in individuals has increased with the advent of the genome era. This complex inflammatory disease has well-defined environmental risk factors. However, in the last 10 years, studies including genome-wide association studies (GWAS) have clearly demonstrated a genetic influence on CAD. Recently, studies on the human Y chromosome have also demonstrated that genetic variation within the male-specific region of the Y chromosome (MSY) could play a part in determining cardiovascular risk in men, confirming the notion that the increased risk for CAD in men cannot be fully explained through common CAD risk factors. Here, we review the literature about the pathophysiology of CAD, its potential causes and environmental risk factors known so far. Furthermore, we review the genetics of CAD, especially the latest discoveries regarding the implication of the Y chromosome, the most underexplored portion of the human genome to date, highlighting methods and difficulties arising in this research field, and discussing the importance of considering the Y chromosome in CAD research.
Epigenetic modifications in essential hypertension
- Wise, Ingrid, Charchar, Fadi
- Authors: Wise, Ingrid , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 17, no. 4 (2016), p. 1-14
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world’s leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual’s risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development. © 2016 by the authors; licensee MDPI, Basel, Switzerland.
- Authors: Wise, Ingrid , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: International Journal of Molecular Sciences Vol. 17, no. 4 (2016), p. 1-14
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. Despite advances in our understanding of the pathophysiology of EH, hypertension remains one of the world’s leading public health problems. Furthermore, there is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH. Indeed, a complex and interactive genetic and environmental system exists to determine an individual’s risk of EH. Epigenetics refers to all heritable changes to the regulation of gene expression as well as chromatin remodelling, without involvement of nucleotide sequence changes. Epigenetic modification is recognized as an essential process in biology, but is now being investigated for its role in the development of specific pathologic conditions, including EH. Epigenetic research will provide insights into the pathogenesis of blood pressure regulation that cannot be explained by classic Mendelian inheritance. This review concentrates on epigenetic modifications to DNA structure, including the influence of non-coding RNAs on hypertension development. © 2016 by the authors; licensee MDPI, Basel, Switzerland.
Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- Pattaro, C, Teumer, A, Gorski, M, Chu, A.Y., Li, M, Mijatovic, V, Garnaas, M, Tin, A, Charchar, Fadi
- Authors: Pattaro, C , Teumer, A , Gorski, M , Chu, A.Y. , Li, M , Mijatovic, V , Garnaas, M , Tin, A , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Communications Vol. 7, no. (2016), p. 1-19
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- Description: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved. Please note that there are two hundred and six authors for this article and we have included only the Federation University Australia affiliate.
- Authors: Pattaro, C , Teumer, A , Gorski, M , Chu, A.Y. , Li, M , Mijatovic, V , Garnaas, M , Tin, A , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Nature Communications Vol. 7, no. (2016), p. 1-19
- Full Text:
- Reviewed:
- Description: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. © 2016, Nature Publishing Group. All rights reserved. Please note that there are two hundred and six authors for this article and we have included only the Federation University Australia affiliate.
Telomere dynamics during aging in polygenic left ventricular hypertrophy
- Marques, Francine, Booth, Scott, Prestes, Priscilla, Curl, Claire, Delbridge, Lea, Lewandowski, Paul, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Booth, Scott , Prestes, Priscilla , Curl, Claire , Delbridge, Lea , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 48, no. 1 (2016), p. 42-49
- Full Text:
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- Description: Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. © 2016 the American Physiological Society.
- Authors: Marques, Francine , Booth, Scott , Prestes, Priscilla , Curl, Claire , Delbridge, Lea , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Physiological Genomics Vol. 48, no. 1 (2016), p. 42-49
- Full Text:
- Reviewed:
- Description: Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk. © 2016 the American Physiological Society.
Telomere length maintenance and cardio-metabolic disease prevention through exercise training
- Denham, Joshua, O'Brien, Brendan, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Sports Medicine Vol. 46, no. 9 (2016), p. 1213-1237
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Telomeres are tandem repeat DNA sequences located at distal ends of chromosomes that protect against genomic DNA degradation and chromosomal instability. Excessive telomere shortening leads to cellular senescence and for this reason telomere length is a marker of biological age. Abnormally short telomeres may culminate in the manifestation of a number of cardio-metabolic diseases. Age-related cardio-metabolic diseases attributable to an inactive lifestyle, such as obesity, type 2 diabetes mellitus and cardiovascular disease, are associated with short leukocyte telomeres. Exercise training prevents and manages the symptoms of many cardio-metabolic diseases whilst concurrently maintaining telomere length. The positive relationship between exercise training, physical fitness and telomere length raises the possibility of a mediating role of telomeres in chronic disease prevention via exercise. Further elucidation of the underpinning molecular mechanisms of how exercise maintains telomere length should provide crucial information on how physical activity can be best structured to combat the chronic disease epidemic and improve the human health span. Here, we synthesise and discuss the current evidence on the impact of physical activity and cardiorespiratory fitness on telomere dynamics. We provide the molecular mechanisms with a known role in exercise-induced telomere length maintenance and highlight unexplored, alternative pathways ripe for future investigations.
- Authors: Denham, Joshua , O'Brien, Brendan , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Sports Medicine Vol. 46, no. 9 (2016), p. 1213-1237
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Telomeres are tandem repeat DNA sequences located at distal ends of chromosomes that protect against genomic DNA degradation and chromosomal instability. Excessive telomere shortening leads to cellular senescence and for this reason telomere length is a marker of biological age. Abnormally short telomeres may culminate in the manifestation of a number of cardio-metabolic diseases. Age-related cardio-metabolic diseases attributable to an inactive lifestyle, such as obesity, type 2 diabetes mellitus and cardiovascular disease, are associated with short leukocyte telomeres. Exercise training prevents and manages the symptoms of many cardio-metabolic diseases whilst concurrently maintaining telomere length. The positive relationship between exercise training, physical fitness and telomere length raises the possibility of a mediating role of telomeres in chronic disease prevention via exercise. Further elucidation of the underpinning molecular mechanisms of how exercise maintains telomere length should provide crucial information on how physical activity can be best structured to combat the chronic disease epidemic and improve the human health span. Here, we synthesise and discuss the current evidence on the impact of physical activity and cardiorespiratory fitness on telomere dynamics. We provide the molecular mechanisms with a known role in exercise-induced telomere length maintenance and highlight unexplored, alternative pathways ripe for future investigations.
Tripartite motif-containing 55 identified as functional candidate for spontaneous cardiac hypertrophy in the rat locus cardiac mass 22
- Prestes, Priscilla, Marques, Francine, Lopez-Campos, Guillermo, Booth, Scott, McGlynn, Maree, Lewandowski, Paul, Delbridge, Lea, Harrap, Stephen, Charchar, Fadi
- Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Booth, Scott , McGlynn, Maree , Lewandowski, Paul , Delbridge, Lea , Harrap, Stephen , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 34, no. 5 (May 2016), p. 950-958
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
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- Description: Background:Left ventricular (LV) hypertrophy is a risk factor for cardiovascular death, but the genetic factors determining LV size and predisposition to hypertrophy are not well understood. We have previously linked the quantitative trait locus cardiac mass 22 (Cm22) on chromosome 2 with cardiac hypertrophy independent of blood pressure in the spontaneously hypertensive rat. From an original cross of spontaneously hypertensive rat with F344 rats, we derived a normotensive polygenic model of spontaneous cardiac hypertrophy, the hypertrophic heart rat (HHR) and its control strain, the normal heart rat (NHR).Methods and results:To identify the genes and molecular mechanisms underlying spontaneous LV hypertrophy we sequenced the HHR genome with special focus on quantitative trait locus Cm22. For correlative analyses of function, we measured global RNA transcripts in LV of neonatal HHR and NHR and 198 neonatal rats of an HHRxNHR F2 crossbred population. Only one gene within locus Cm22 was differentially expressed in the parental generation: tripartite motif-containing 55 (Trim55), with mRNA downregulation in HHR (P<0.05) and reduced protein expression. Trim55 mRNA levels were negatively correlated with LV mass in the F2 cross (r=-0.16, P=0.025). In exon nine of Trim55 in HHR, we found one missense mutation that functionally alters protein structure. This mutation was strongly associated with Trim55 mRNA expression in F2 rats (F=10.35, P<0.0001). Similarly, in humans, we found reduced Trim55 expression in hearts of subjects with idiopathic dilated cardiomyopathy.Conclusion:Our study suggests that the Trim55 gene, located in Cm22, is a novel candidate gene for polygenic LV hypertrophy independent of blood pressure.
- Authors: Prestes, Priscilla , Marques, Francine , Lopez-Campos, Guillermo , Booth, Scott , McGlynn, Maree , Lewandowski, Paul , Delbridge, Lea , Harrap, Stephen , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 34, no. 5 (May 2016), p. 950-958
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
- Full Text:
- Reviewed:
- Description: Background:Left ventricular (LV) hypertrophy is a risk factor for cardiovascular death, but the genetic factors determining LV size and predisposition to hypertrophy are not well understood. We have previously linked the quantitative trait locus cardiac mass 22 (Cm22) on chromosome 2 with cardiac hypertrophy independent of blood pressure in the spontaneously hypertensive rat. From an original cross of spontaneously hypertensive rat with F344 rats, we derived a normotensive polygenic model of spontaneous cardiac hypertrophy, the hypertrophic heart rat (HHR) and its control strain, the normal heart rat (NHR).Methods and results:To identify the genes and molecular mechanisms underlying spontaneous LV hypertrophy we sequenced the HHR genome with special focus on quantitative trait locus Cm22. For correlative analyses of function, we measured global RNA transcripts in LV of neonatal HHR and NHR and 198 neonatal rats of an HHRxNHR F2 crossbred population. Only one gene within locus Cm22 was differentially expressed in the parental generation: tripartite motif-containing 55 (Trim55), with mRNA downregulation in HHR (P<0.05) and reduced protein expression. Trim55 mRNA levels were negatively correlated with LV mass in the F2 cross (r=-0.16, P=0.025). In exon nine of Trim55 in HHR, we found one missense mutation that functionally alters protein structure. This mutation was strongly associated with Trim55 mRNA expression in F2 rats (F=10.35, P<0.0001). Similarly, in humans, we found reduced Trim55 expression in hearts of subjects with idiopathic dilated cardiomyopathy.Conclusion:Our study suggests that the Trim55 gene, located in Cm22, is a novel candidate gene for polygenic LV hypertrophy independent of blood pressure.
A meta-analysis of gene expression signatures of blood pressure and hypertension
- Authors: Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: PLoS Genetics Vol. 11, no. 3 (2015), p. 1-29
- Full Text:
- Reviewed:
- Description: Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension. **Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliate is provided in this record**
- Authors: Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: PLoS Genetics Vol. 11, no. 3 (2015), p. 1-29
- Full Text:
- Reviewed:
- Description: Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension. **Please note that there are multiple authors for this article therefore only the name of the Federation University Australia affiliate is provided in this record**
Contribution of microRNA to pathological fibrosis in cardiorenal syndrome : Impact of uremic toxins
- Rana, Indrajeetsinh, Kompa, Andrew, Skommer, Joanna, Wang, Bing, Lekawanvijit, Suree, Kelly, Darren, Krum, Henry, Charchar, Fadi
- Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
- Full Text:
- Reviewed:
- Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.
- Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
- Full Text:
- Reviewed:
- Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.
Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans
- Denham, Joshua, O'Brien, Brendan, Harvey, Jack, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Harvey, Jack , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Epigenomics Vol. 7, no. 5 (2015), p. 717-731
- Full Text:
- Reviewed:
- Description: Aim: DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation. Materials & methods: Twenty-four men were recruited and assigned to an exercise intervention or control group. Clinical parameters were measured and sperm samples were donated by subjects before and after the 3-month time-period. Mature sperm global and genome-wide DNA methylation was assessed using an ELISA assay and the 450K BeadChip (Illumina). Results: Global and genome-wide sperm DNA methylation was altered after 3 months of exercise training. DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson's disease. Conclusions: Our study provides the first evidence showing exercise training reprograms the sperm methylome. Whether these DNA methylation changes are inherited to future generations warrants attention.
- Authors: Denham, Joshua , O'Brien, Brendan , Harvey, Jack , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Epigenomics Vol. 7, no. 5 (2015), p. 717-731
- Full Text:
- Reviewed:
- Description: Aim: DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation. Materials & methods: Twenty-four men were recruited and assigned to an exercise intervention or control group. Clinical parameters were measured and sperm samples were donated by subjects before and after the 3-month time-period. Mature sperm global and genome-wide DNA methylation was assessed using an ELISA assay and the 450K BeadChip (Illumina). Results: Global and genome-wide sperm DNA methylation was altered after 3 months of exercise training. DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson's disease. Conclusions: Our study provides the first evidence showing exercise training reprograms the sperm methylome. Whether these DNA methylation changes are inherited to future generations warrants attention.
Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres
- Denham, Joshua, O'Brien, Brendan, Prestes, Priscilla, Brown, Nicholas, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Prestes, Priscilla , Brown, Nicholas , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 120, no. 2 (2015), p. 148-158
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative (V) over dotO(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.
- Authors: Denham, Joshua , O'Brien, Brendan , Prestes, Priscilla , Brown, Nicholas , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 120, no. 2 (2015), p. 148-158
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative (V) over dotO(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.
Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure
- Tomaszewski, Maciej, Eales, James, Denniff, Matthew, Myers, Stephen, Chew, Guatsiew, Nelson, Christopher, Christofidou, Paraskevi, Desai, Aishwarya, Büsst, Cara, Wojnar, Lukasz, Musialik, Katarzyna, Jozwiak, Jacek, Debiec, Radoslaw, Dominiczak, Anna, Navis, Gerjan, van Gilst, Wiek, van der Harst, Pim, Samani, Nilesh, Harrap, Stephen, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Charchar, Fadi
- Authors: Tomaszewski, Maciej , Eales, James , Denniff, Matthew , Myers, Stephen , Chew, Guatsiew , Nelson, Christopher , Christofidou, Paraskevi , Desai, Aishwarya , Büsst, Cara , Wojnar, Lukasz , Musialik, Katarzyna , Jozwiak, Jacek , Debiec, Radoslaw , Dominiczak, Anna , Navis, Gerjan , van Gilst, Wiek , van der Harst, Pim , Samani, Nilesh , Harrap, Stephen , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of the American Society of Nephrology Vol. 26, no. 12 (2015), p. 3151-3160
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65 x10(-5)) and diastolic BP (P=7.61 x10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0x10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.
- Authors: Tomaszewski, Maciej , Eales, James , Denniff, Matthew , Myers, Stephen , Chew, Guatsiew , Nelson, Christopher , Christofidou, Paraskevi , Desai, Aishwarya , Büsst, Cara , Wojnar, Lukasz , Musialik, Katarzyna , Jozwiak, Jacek , Debiec, Radoslaw , Dominiczak, Anna , Navis, Gerjan , van Gilst, Wiek , van der Harst, Pim , Samani, Nilesh , Harrap, Stephen , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of the American Society of Nephrology Vol. 26, no. 12 (2015), p. 3151-3160
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65 x10(-5)) and diastolic BP (P=7.61 x10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0x10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.
Acute exercise leads to regulation of Telomere-Associated genes and MicroRNA expression in immune Cells
- Chilton, Warrick, Marques, Francine, West, Jenny, Kannourakis, George, Berzins, Stuart, O'Brien, Brendan, Charchar, Fadi
- Authors: Chilton, Warrick , Marques, Francine , West, Jenny , Kannourakis, George , Berzins, Stuart , O'Brien, Brendan , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: PloS One Vol. 9, no. 4 (2014), p. e92088
- Full Text:
- Reviewed:
- Description: Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health. Funding NHMRC
- Authors: Chilton, Warrick , Marques, Francine , West, Jenny , Kannourakis, George , Berzins, Stuart , O'Brien, Brendan , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: PloS One Vol. 9, no. 4 (2014), p. e92088
- Full Text:
- Reviewed:
- Description: Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health. Funding NHMRC