121 Telomere attrition is attenuated in ultra-marathon runners
- Denham, Joshua, Nankervis, Scott, Debiec, Radek, Harvey, Jack, Pascoe, Deborah, Marques, Francine, O’Brien, Brendan, Zukowska-Szczechowska, Ewa, Tomaszewski, Maciej, Charchar, Fadi
- Authors: Denham, Joshua , Nankervis, Scott , Debiec, Radek , Harvey, Jack , Pascoe, Deborah , Marques, Francine , O’Brien, Brendan , Zukowska-Szczechowska, Ewa , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 30, no. e-Supplement (September 2012), p. e37
- Full Text: false
- Reviewed:
- Description: Background: Leukocyte telomere length is a marker of biological ageing and its shortening is associated with cardiovascular disease. Engagement in regular moderate-intensity physical activity is a recognised method of cardiovascular disease prevention. However, it is not clear whether repeated exposure to ultra-strenuous physical exercise is beneficial long-term and whether it may attenuate biological ageing. Methods: We compared leukocyte telomere length in context of inflammation and endothelial dysfunction between 67 male ultra-marathon runners and 67 age-, sex- and BMI-matched apparently healthy controls. Genomic DNA was extracted from peripheral blood and leukocyte telomere length was measured by quantitative polymerase chain reaction assays. Adhesion molecules (sICAM-1, sE-selectin) and inflammatory markers (IL-6, C-reactive protein) concentrations were measured in 67 ultra-marathon runners by quantitative sandwich enzyme immunoassay technique, high-sensitive immunoassay and ultra-sensitive double antibody sandwich ELISA, respectively. Results: Adjusted (for age, BMI, blood pressure and lipids) leukocyte telomere length was approximately 13.8% greater in the ultra-marathon runners than in the controls (P<0.001). This translates into approximately 32.9 years difference in age-related telomere length attrition. There was a strong negative linear correlation between sICAM-1 and leukocyte telomere length in the ultra-marathon runners (r=-0.33; P=0.007) and this association retained its statistical significance after adjustment for age, BMI, blood pressure and lipids in multiple regression (P=0.026). Conclusion: Prolonged, intense physical exercise may attenuate cellular ageing possibly through a protective effect on endothelial function.
- Description: C1
- Jackson, Kristy, Marques, Francine, Watson, Anna, Palma-Rigo, Keisia, Nguyen-Huu, Thu-Phuc, Morris, Brian, Charchar, Fadi, Davern, Pamela, Head, Geoffrey
- Authors: Jackson, Kristy , Marques, Francine , Watson, Anna , Palma-Rigo, Keisia , Nguyen-Huu, Thu-Phuc , Morris, Brian , Charchar, Fadi , Davern, Pamela , Head, Geoffrey
- Date: 2013
- Type: Text , Journal article
- Relation: Hypertension Vol. 62 , no. 4 (2013), p. 775-781
- Full Text: false
- Reviewed:
- Description: Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.
Abnormal microRNA expression in cardiac hypertrophy and the regulation of the Endog gene
- Quarrell, Sean, Marques, Francine, Jayaswal, Vivek, Curl, Claire, Nankervis, Scott, Yang, Jean, Delbridge, Lea, Harrap, Stephen, Charchar, Fadi
- Authors: Quarrell, Sean , Marques, Francine , Jayaswal, Vivek , Curl, Claire , Nankervis, Scott , Yang, Jean , Delbridge, Lea , Harrap, Stephen , Charchar, Fadi
- Date: 2012
- Type: Text , Journal article
- Relation: Heart, Lung and Circulation Vol. 21, no. Supplement 1 (2012), p. s7
- Full Text: false
- Reviewed:
- Description: A deficiency in the gene for endonuclease G (Endog) was recently described as a genetic determinant of cardiac hypertrophy. The mechanisms involved in the regulation of Endog, however, are still to be elucidated. Therefore we hypothesised that Endog, being regulated by small regulatory non-coding RNAs called microRNAs (miRNAs), could contribute to the cardiac hypertrophy of the Hypertrophic Heart Rat (HHR), a human polygenic model of cardiac hypertrophy. From birth the HHR has less and smaller cardiomyocytes, which leads to hypertrophy and cardiac failure later in life. In this study, we examined genome-wide miRNA expression by Agilent Rat miRNA Microarray Kit Release 16.0 and Endog mRNA levels by real-time PCR in the left ventricle of neonatal HHR compared to age-matched rats from its authentic control, the Normal Heart Rat (NHR). Endog mRNA was significantly under-expressed in the HHR (fold change=−4.7; P=0.0001). Sixty-seven miRNAs (FDR P<0.05 and fold change>1.1) were differentially expressed between HHR and NHR (n=16). We then performed an in silico analysis to predict the miRNAs that are able to bind to the 3′ untranslated region of Endog mRNA, and therefore could regulate Endog levels. We discovered that the miRNAs let-7b, miR-338 and miR-347 are predicted to bind to Endog mRNA. Functional studies are being undertaken to determine whether these miRNAs can regulate Endog mRNA levels in vitro and their role in the pathological processes leading to cardiac hypertrophy. These miRNAs could be a new target for the prevention and treatment of cardiac hypertrophy in humans
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
Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise
- Denham, Joshua, O'Brien, Brendan, Marques, Francine, Charchar, Fadi
- Authors: Denham, Joshua , O'Brien, Brendan , Marques, Francine , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 118, no. 4 (2015), p. 475-488
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Physical exercise has proven cardiovascular benefits, yet there is no clear understanding of the related molecular mechanisms leading to this. Here we determined the beneficial epigenetic effects of exercise after sprint interval training, a form of exercise known to improve cardiometabolic health. We quantified genome-wide leukocyte DNA methylation of 12 healthy young (18-24 yr) men before and after 4 wk (thrice weekly) of sprint interval training using the 450K BeadChip (Illumina) and validated gene expression changes in an extra seven subjects. Exercise increased subjects' cardiorespiratory fitness and maximal running performance, and decreased low-density lipoprotein cholesterol concentration in conjunction with genome-wide DNA methylation changes. Notably, many CpG island and gene promoter regions were demethylated after exercise, indicating increased genome-wide transcriptional changes. Among genes with DNA methylation changes, epidermal growth factor (EGF), a ligand of the epidermal growth factor receptor known to be involved in cardiovascular disease, was demethylated and showed decreased mRNA expression. Additionally, we found that in microRNAs miR-21 and miR-210, gene DNA methylation was altered by exercise causing a cascade effect on the expression of the mature microRNA involved in cardiovascular function. Our findings demonstrate that exercise alters DNA methylation in circulating blood cells in microRNA and protein-coding genes associated with cardiovascular physiology. Copyright © 2015 the American Physiological Society
Deficiency of MicroRNA-181a results in transcriptome-wide cell-specific changes in the kidney and increases blood pressure
- Paterson, Madeleine, Jackson, Kristy, Dona, Malathi, Farrugia, Gabriella, Visniauskas, Bruna, Watson, Anna, Johnson, Chad, Prieto, Minolfa, Evans, Roger, Charchar, Fadi, Pinto, Alexander, Marques, Francine, Head, Geoffrey
- Authors: Paterson, Madeleine , Jackson, Kristy , Dona, Malathi , Farrugia, Gabriella , Visniauskas, Bruna , Watson, Anna , Johnson, Chad , Prieto, Minolfa , Evans, Roger , Charchar, Fadi , Pinto, Alexander , Marques, Francine , Head, Geoffrey
- Date: 2021
- Type: Text , Journal article
- Relation: Hypertension Vol. 78, no. 5 (Nov 2021), p. 1322-1334
- Full Text:
- Reviewed:
- Description: MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours (P<0.01). Compared with WT mice, renal renin was higher in the juxtaglomerular cells of KO mice. BP was similar in WT mice on a high- (3.1%) versus low- (0.3%) sodium diet (+0.4 +/- 0.8 mm Hg), but KO mice showed salt sensitivity (+3.3 +/- 0.8 mm Hg; P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA sequencing in 6699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, and Smad4. We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.
- Authors: Paterson, Madeleine , Jackson, Kristy , Dona, Malathi , Farrugia, Gabriella , Visniauskas, Bruna , Watson, Anna , Johnson, Chad , Prieto, Minolfa , Evans, Roger , Charchar, Fadi , Pinto, Alexander , Marques, Francine , Head, Geoffrey
- Date: 2021
- Type: Text , Journal article
- Relation: Hypertension Vol. 78, no. 5 (Nov 2021), p. 1322-1334
- Full Text:
- Reviewed:
- Description: MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours (P<0.01). Compared with WT mice, renal renin was higher in the juxtaglomerular cells of KO mice. BP was similar in WT mice on a high- (3.1%) versus low- (0.3%) sodium diet (+0.4 +/- 0.8 mm Hg), but KO mice showed salt sensitivity (+3.3 +/- 0.8 mm Hg; P<0.001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA sequencing in 6699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, and Smad4. We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.
- Marques, Francine, Prestes, Priscilla, Lewandowski, Paul, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Prestes, Priscilla , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2015
- Type: Text , Conference paper
- Relation: Cardiac Society of Australia and New Zealand Annual Scientific Meeting and the International Society for Heart Research Australasian Section Annual Scientific Meeting; Melbourne, Victoria, Australia; 13th-16th August 2016; published in Heart, Lung and Circulation. Vol. 24, p. S401-S401
- Full Text: false
- Reviewed:
- Description: Objective: The molecular processes associated with cardiac hypertrophy independent of blood pressure are still largely unknown. The hypertrophic heart rate (HHR) is normotensive and born with a reduced complement of cardiomyocytes that predisposes to cardiac hypertrophy and failure in later life. We investigated the expression of c-kit gene, a marker of cardiac stem cells and myocardial regeneration that could contribute to hypertrophy. Methods: Left ventricular c-kit mRNA expression was measured by real-time PCR in HHR and control strain in neonatal and 38-week old rats (n=7-12/group). We tested for linkage of c-kit expression with neonatal cardiac size in 197 second generation crosses (F2) of HHR and control strain. Results: c-kit mRNA was slightly up-regulated in neonatal (fold change +1.3, P=0.02) and markedly so in 38-week old HHR (+35.5, P=0.0003). Cardiac weight index was positively correlated with neonatal myocardial c-kit mRNA in the F2 population (r=0.19, P=0.007). Conclusions: In HHR hearts c-kit expression appears increased throughout life, but more so in the adult where cardiac hypertrophy is established and leading to failure. In aged hypertrophic hearts, over-expression of c-kit is likely a compensatory mechanism of the failing heart. Previous studies showed an activation of cardiac stem cells in the hypertrophic myocardium. Our study suggests that c-kit might be involved from an early age in mechanisms that lead to cardiac hypertrophy in adulthood.
Epigenetic changes in leukocytes after 8 weeks of resistance exercise training
- Denham, Joshua, Marques, Francine, Bruns, Emma, O'Brien, Brendan, Charchar, Fadi
- Authors: Denham, Joshua , Marques, Francine , Bruns, Emma , O'Brien, Brendan , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: European Journal of Applied Physiology Vol. 116, no. 6 (2016), p. 1245-1253
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: PURPOSE: Regular engagement in resistance exercise training elicits many health benefits including improvement to muscular strength, hypertrophy and insulin sensitivity, though the underpinning molecular mechanisms are poorly understood. The purpose of this study was to determine the influence 8 weeks of resistance exercise training has on leukocyte genome-wide DNA methylation and gene expression in healthy young men. METHODS: Eight young (21.1 +/- 2.2 years) men completed one repetition maximum (1RM) testing before completing 8 weeks of supervised, thrice-weekly resistance exercise training comprising three sets of 8-12 repetitions with a load equivalent to 80 % of 1RM. Blood samples were collected at rest before and after the 8-week training intervention. Genome-wide DNA methylation and gene expression were assessed on isolated leukocyte DNA and RNA using the 450K BeadChip and HumanHT-12 v4 Expression BeadChip (Illumina), respectively. RESULTS: Resistance exercise training significantly improved upper and lower body strength concurrently with diverse genome-wide DNA methylation and gene expression changes (p = 0. 01). DNA methylation changes occurred at multiple regions throughout the genome in context with genes and CpG islands, and in genes relating to axon guidance, diabetes and immune pathways. There were multiple genes with increased expression that were enriched for RNA processing and developmental proteins. Growth factor genes-GHRH and FGF1-showed differential methylation and mRNA expression changes after resistance training. CONCLUSIONS: Our findings indicate that resistance exercise training improves muscular strength and is associated with reprogramming of the leukocyte DNA methylome and transcriptome.
Exercise : Putting action into our epigenome
- Denham, Joshua, Marques, Francine, O'Brien, Brendan, Charchar, Fadi
- Authors: Denham, Joshua , Marques, Francine , O'Brien, Brendan , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: Sports Medicine Vol. 44, no. 2 (2014), p. 189-209
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Most human phenotypes are influenced by a combination of genomic and environmental factors. Engaging in regular physical exercise prevents many chronic diseases, decreases mortality risk and increases longevity. However, the mechanisms involved are poorly understood. The modulating effect of physical (aerobic and resistance) exercise on gene expression has been known for some time now and has provided us with an understanding of the biological responses to physical exercise. Emerging research data suggest that epigenetic modifications are extremely important for both development and disease in humans. In the current review, we summarise findings on the effect of exercise on epigenetic modifications and their effects on gene expression. Current research data suggest epigenetic modifications (DNA methylation and histone acetylation) and microRNAs (miRNAs) are responsive to acute aerobic and resistance exercise in brain, blood, skeletal and cardiac muscle, adipose tissue and even buccal cells. Six months of aerobic exercise alters whole-genome DNA methylation in skeletal muscle and adipose tissue and directly influences lipogenesis. Some miRNAs are related to maximal oxygen consumption (VO 2max) and VO2max trainability, and are differentially expressed amongst individuals with high and low VO2max. Remarkably, miRNA expression profiles discriminate between low and high responders to resistance exercise (miR-378, -26a, -29a and -451) and correlate to gains in lean body mass (miR-378). The emerging field of exercise epigenomics is expected to prosper and additional studies may elucidate the clinical relevance of miRNAs and epigenetic modifications, and delineate mechanisms by which exercise confers a healthier phenotype and improves performance. © 2013 Springer International Publishing Switzerland. Funded by NHMRC; National Health and Medical Research Council
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.
- Marques, Francine, Campain, Anna, Tomaszewski, Maciej, Zukowska-Szczechowska, Ewa, Yang, Yee, Charchar, Fadi, Morris, Brian
- Authors: Marques, Francine , Campain, Anna , Tomaszewski, Maciej , Zukowska-Szczechowska, Ewa , Yang, Yee , Charchar, Fadi , Morris, Brian
- Date: 2011
- Type: Text , Journal article
- Relation: Hypertension Vol. 58, no. 6 (2011), p. 1093-1098
- Full Text: false
- Reviewed:
- Description: The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1, NR4A2, NR4A3, PER1, and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3' untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1, AMBP, APOE, CD36, EFNB1, NDUFAF1, PRDX5, REN, RENBP, SLC13A1, STX4, and TNNT2 mRNAs and for miRNAs hsa-miR-21, hsa-miR-126, hsa-miR-181a, hsa-miR-196a, hsa-miR-451, hsa-miR-638, and hsa-miR-663. Functional experiments in HEK293 cells demonstrated that hsa-miR-663 can bind to the REN and APOE 3' untranslated regions and can regulate REN and APOE mRNA levels, whereas hsa-miR-181a regulated REN and AIFM1 mRNA. Our data demonstrated for the first time that miRNAs can regulate renin expression. The observed downregulation of 2 miRNAs in hypertension could explain the elevation in intrarenal renin mRNA. Renin, CD36, and other mRNAs, as well as miRNAs and associated pathways identified in the present study, provide novel insights into hypertension etiology. © 2011 American Heart Association, Inc.
Genetic mechanisms of vascular and renal damage
- Marques, Francine, Tomaszewski, Maciej, Charchar, Fadi
- Authors: Marques, Francine , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2013
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 31, no. 11 (2013), p. 2128-2129
- Full Text: false
- Reviewed:
- Description: Document type (note)
- Description: C4
Highlights from the International Society of Hypertension's New Investigators Network during 2019
- Kruger, Ruan, Brunström, Mattias, Burger, Dylan, Charchar, Fadi, Climie, Rachel, Mirabito, Colafell, Kempny, Katrina, Korostovtseva, Lyudimila, Marques, Francine, Picone, Dean, Romero, Cesar, Steckelings, Ulrike, Velkoska, Elena, Wainford, Richard, Wynne, Brandi, Zanuzzi, Matias
- Authors: Kruger, Ruan , Brunström, Mattias , Burger, Dylan , Charchar, Fadi , Climie, Rachel , Mirabito, Colafell , Kempny, Katrina , Korostovtseva, Lyudimila , Marques, Francine , Picone, Dean , Romero, Cesar , Steckelings, Ulrike , Velkoska, Elena , Wainford, Richard , Wynne, Brandi , Zanuzzi, Matias
- Date: 2020
- Type: Text , Journal article
- Relation: Journal of hypertension Vol. 38, no. 5 (2020), p. 968-973
- Full Text: false
- Reviewed:
- Description: The New Investigators Committee (NIC) of the International Society of Hypertension (ISH) is a dynamic group of junior doctors and scientists, actively involved in various society activities. This report highlights the events (scientific meetings and summer schools) and activities (social media, mentorship and networking) during 2019 including May Measurement Month and collaborative efforts with the ISH Women in Hypertension Research Committee (WiHRC). The ISH NIC is proud to sponsor awards for outstanding work by junior and emerging researchers at hypertension conferences and also provides opportunities to showcase their work on our social media features such as 'Our Fellows Work' and the New Investigator Spotlight of the month. In 2020, the ISH NIC aims to promote women in leadership roles and to foster strong collaborations with and between society committees and other scientific organizations.
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.
Leukocyte telomere length variation due to DNA extraction method
- Denham, Joshua, Marques, Francine, Charchar, Fadi
- Authors: Denham, Joshua , Marques, Francine , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: BMC research notes Vol. 7, no. (2014), p. 877
- Full Text: false
- Reviewed:
- Description: Telomere length is indicative of biological age. Shorter telomeres have been associated with several disease and health states. There are inconsistencies throughout the literature amongst relative telomere length measured by quantitative PCR (qPCR) and different extraction methods or kits used. We quantified whole-blood leukocyte telomere length using the telomere to single copy gene (T/S) ratio by qPCR in 20 young (18-25 yrs) men after extracting DNA using three common extraction methods: Lahiri and Nurnberger (high salt) method, PureLink Genomic DNA Mini kit (Life Technologies) and QiaAmp DNA Mini kit (Qiagen). Telomere length differences of DNA extracted from the three extraction methods was assessed by one-way analysis of variance (ANOVA).
Lifestyle management of hypertension : International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension
- Charchar, Fadi, Prestes, Priscilla, Mills, Charlotte, Ching, Siew, Neupane, Dinesh, Marques, Francine, Sharman, James, Vogt, Liffert, Burrell, Louise, Korostovtseva, Lyudmila, Zec, Manja, Patil, Mansi, Schultz, Martin, Wallen, Matthew, Renna, Nicolás, Islam, Sheikh, Hiremath, Swapnil, Gyeltshen, Tshewang, Chia, Yook-Chin, Gupta, Abhinav, Schutte, Aletta, Klein, Britt, Borghi, Claudio, Browning, Colette, Czesnikiewicz-Guzik, Marta, Lee, Hae-Young, Itoh, Hiroshi, Miura, Katsuyuki, Akinnibosun, Olutope, Shane Thomas
- Authors: Charchar, Fadi , Prestes, Priscilla , Mills, Charlotte , Ching, Siew , Neupane, Dinesh , Marques, Francine , Sharman, James , Vogt, Liffert , Burrell, Louise , Korostovtseva, Lyudmila , Zec, Manja , Patil, Mansi , Schultz, Martin , Wallen, Matthew , Renna, Nicolás , Islam, Sheikh , Hiremath, Swapnil , Gyeltshen, Tshewang , Chia, Yook-Chin , Gupta, Abhinav , Schutte, Aletta , Klein, Britt , Borghi, Claudio , Browning, Colette , Czesnikiewicz-Guzik, Marta , Lee, Hae-Young , Itoh, Hiroshi , Miura, Katsuyuki , Akinnibosun, Olutope , Shane Thomas
- Date: 2024
- Type: Text , Journal article
- Relation: Journal of hypertension Vol. 42, no. 1 (2024), p. 23-49
- Full Text:
- Reviewed:
- Description: Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Fadi Charchar, Priscilla Prestes, Britt Klein, Colette Browning, Olutope Akinnibosun and Shane Thomas” are provided in this record**
- Description: Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Fadi Charchar, Priscilla Prestes, Britt Klein, Colette Browning, Olutope Akinnibossun and Shane Thomas” are provided in this record**
- Authors: Charchar, Fadi , Prestes, Priscilla , Mills, Charlotte , Ching, Siew , Neupane, Dinesh , Marques, Francine , Sharman, James , Vogt, Liffert , Burrell, Louise , Korostovtseva, Lyudmila , Zec, Manja , Patil, Mansi , Schultz, Martin , Wallen, Matthew , Renna, Nicolás , Islam, Sheikh , Hiremath, Swapnil , Gyeltshen, Tshewang , Chia, Yook-Chin , Gupta, Abhinav , Schutte, Aletta , Klein, Britt , Borghi, Claudio , Browning, Colette , Czesnikiewicz-Guzik, Marta , Lee, Hae-Young , Itoh, Hiroshi , Miura, Katsuyuki , Akinnibosun, Olutope , Shane Thomas
- Date: 2024
- Type: Text , Journal article
- Relation: Journal of hypertension Vol. 42, no. 1 (2024), p. 23-49
- Full Text:
- Reviewed:
- Description: Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Fadi Charchar, Priscilla Prestes, Britt Klein, Colette Browning, Olutope Akinnibosun and Shane Thomas” are provided in this record**
- Description: Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools. **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliates “Fadi Charchar, Priscilla Prestes, Britt Klein, Colette Browning, Olutope Akinnibossun and Shane Thomas” are provided in this record**
Longer leukocyte telomeres are associated with ultra-endurance exercise independent of cardiovascular risk factors
- Denham, Joshua, Nelson, Christopher, O'Brien, Brendan, Nankervis, Scott, Denniff, Matthew, Harvey, Jack, Marques, Francine, Codd, Veryan, Zukowska-Szczechowska, Ewa, Samani, Nilesh, Tomaszewski, Maciej, Charchar, Fadi
- Authors: Denham, Joshua , Nelson, Christopher , O'Brien, Brendan , Nankervis, Scott , Denniff, Matthew , Harvey, Jack , Marques, Francine , Codd, Veryan , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS ONE Vol. 8, no. 7 (2013), p.
- Full Text:
- Reviewed:
- Description: Telomere length is recognized as a marker of biological age, and shorter mean leukocyte telomere length is associated with increased risk of cardiovascular disease. It is unclear whether repeated exposure to ultra-endurance aerobic exercise is beneficial or detrimental in the long-term and whether it attenuates biological aging. We quantified 67 ultra-marathon runners' and 56 apparently healthy males' leukocyte telomere length (T/S ratio) using real-time quantitative PCR. The ultra-marathon runners had 11% longer telomeres (T/S ratio) than controls (ultra-marathon runners: T/S ratio = 3.5±0.68, controls: T/S ratio = 3.1±0.41;
- Description: 2003011219
- Authors: Denham, Joshua , Nelson, Christopher , O'Brien, Brendan , Nankervis, Scott , Denniff, Matthew , Harvey, Jack , Marques, Francine , Codd, Veryan , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS ONE Vol. 8, no. 7 (2013), p.
- Full Text:
- Reviewed:
- Description: Telomere length is recognized as a marker of biological age, and shorter mean leukocyte telomere length is associated with increased risk of cardiovascular disease. It is unclear whether repeated exposure to ultra-endurance aerobic exercise is beneficial or detrimental in the long-term and whether it attenuates biological aging. We quantified 67 ultra-marathon runners' and 56 apparently healthy males' leukocyte telomere length (T/S ratio) using real-time quantitative PCR. The ultra-marathon runners had 11% longer telomeres (T/S ratio) than controls (ultra-marathon runners: T/S ratio = 3.5±0.68, controls: T/S ratio = 3.1±0.41;
- Description: 2003011219
Measurement of absolute copy number variation reveals association with essential hypertension
- Marques, Francine, Prestes, Priscilla, Pinheiro, Leonardo, Scurrah, Katrina, Emslie, Kerry, Tomaszewski, Maciej, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Prestes, Priscilla , Pinheiro, Leonardo , Scurrah, Katrina , Emslie, Kerry , Tomaszewski, Maciej , Harrap, Stephen , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: BMC Medical Genomics Vol. 7, no. (2014), p. 1-8
- Full Text:
- Reviewed:
- Description: Background: The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR. Methods: Using a "power of extreme" approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random. Results: A deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013). Conclusions: Our data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension.
- Authors: Marques, Francine , Prestes, Priscilla , Pinheiro, Leonardo , Scurrah, Katrina , Emslie, Kerry , Tomaszewski, Maciej , Harrap, Stephen , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: BMC Medical Genomics Vol. 7, no. (2014), p. 1-8
- Full Text:
- Reviewed:
- Description: Background: The role of copy number variation (CNV) has been poorly explored in essential hypertension in part due to technical difficulties in accurately assessing absolute numbers of DNA copies. Droplet digital PCR (ddPCR) provides a powerful new approach to CNV quantitation. The aim of our study was to investigate whether CNVs located in regions previously associated with blood pressure (BP) variation in genome-wide association studies (GWAS) were associated with essential hypertension by the use of ddPCR. Methods: Using a "power of extreme" approach, we quantified nucleic acids using ddPCR in white subjects from the Victorian Family Heart Study with extremely high (n = 96) and low (n = 92) SBP, providing power equivalent to 1714 subjects selected at random. Results: A deletion of the CNVs esv27061 and esv2757747 on chromosome 1p13.2 was significantly more prevalent in extreme high BP subjects after adjustment for age, body mass index and sex (12.6% vs. 2.2%; P = 0.013). Conclusions: Our data suggests that CNVs within regions identified in previous GWAS may play a role in human essential hypertension.
- Booth, Scott, Marques, Francine, Prestes, Priscilla, Curl, Claire, Delbridge, Lea, Lewandowski, Paul, Harrap, Stephen, Charchar, Fadi
- Authors: Booth, Scott , Marques, Francine , Prestes, Priscilla , Curl, Claire , Delbridge, Lea , Lewandowski, Paul , Harrap, Stephen , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Heart, Lung and Circulation Vol. 24, no. S3 (2015), p. S180-S181
- Full Text: false
- Reviewed:
- Description: Cardiac hypertrophy is one of the main risk factors forheart failure. Here we aimed to investigate whether cardiactelomere length contributes to polygenic cardiac hypertro-phy independent of blood pressure. We also investigatedwhether changes in telomere length were due to the telomereregulators microRNA-34a,Ppp1r10(also known asPnuts)and telomerase. We used the hypertrophic heart rat (HHR),a normotensive model of polygenetic cardiac hypertrophy,and compared it to age-matched controls. Telomere length, microRNA levels, gene expression and telomerase activitywere measured in isolated cardiomyocytes and left ventricletissue using real-time PCR. Telomere length was significantlylonger in 2-day and 38-week-old HHR, but shorter at 4-and 13-week HHR. In the HHR, telomere length becameshorter early in development, while in the control straintelomere shortening was only observed in late adulthood.Telomere length was the main determinant of cardiac mass.
MicroRNAs in essential hypertension and blood pressure regulation
- Marques, Francine, Charchar, Fadi
- Authors: Marques, Francine , Charchar, Fadi
- Date: 2015
- Type: Text , Book chapter
- Relation: Advances in Experimental Medicine and Biology p. 215-235
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: Unravelling the complete genetic predisposition to high blood pressure (BP) has proven to be challenging. This puzzle and the fact that coding regions of the genome account for less than 2 % of the entire human DNA support the hypothesis that mechanisms besides coding genes are likely to contribute to BP regulation. Non-coding RNAs, especially microRNAs, are emerging as key players of transcription regulation in both health and disease states. They control basic functions in virtually all cell types relevant to the cardiovascular system and, thus, a direct involvement with BP regulation is highly probable. Here we review the literature about microRNAs associated with regulation of BP and hypertension, highlighting investigations, methodology and difficulties arising in the field. These molecules are being studied for exploitation in diagnostics, prognostics and therapeutics in many diseases. There have been some studies that examined biological fl uid microRNAs as biomarkers for hypertension, but most remain inconclusive due to the small sample sizes and differences in methodological standardisation. Fewer studies have analysed tissue microRNA levels in vascular smooth muscle cells and the kidney. Others focused on the interaction between single nucleotide polymorphisms and microRNA binding sites. Studies in animals have shown that angiotensin II, high- salt diet and exercise change microRNA levels in hypertension. Treatment of spontaneously hypertensive rats with a miR-22 inhibitor and treatment of hypertensive Schlager BPH/2J mice with a miR-181a mimic decreased their BP. This supports the use of microRNAs as therapeutic targets in hypertension, and future studies should test the use of other microRNAs found in human association studies. In conclusion, there is a clear need of increased pace of human, animal and functional studies to help us understand the multifaceted roles of microRNAs as critical regulators of the development and physiology of BP. © Springer International Publishing Switzerland 2015. Funding Details: APP1052659, NHMRC, National Heart Foundation of Australia Funding Details: PF12M6785, National Heart Foundation of Australia