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
- 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.
- 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.
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.
- Rodriguez, Blanca Morales, Khouzami, Lara, Decostre, Valérie, Varnous, Shaida, Pekovic-Vaughan, Vanja, Hutchison, Christopher, Pecker, Françoise, Bonne, Gisèle, Muchir, Antoine
- Authors: Rodriguez, Blanca Morales , Khouzami, Lara , Decostre, Valérie , Varnous, Shaida , Pekovic-Vaughan, Vanja , Hutchison, Christopher , Pecker, Françoise , Bonne, Gisèle , Muchir, Antoine
- Date: 2018
- Type: Text , Journal article
- Relation: Human Molecular Genetics Vol. 27, no. 19 (2018), p. 3353-3360
- Full Text: false
- Reviewed:
- Description: Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscular and electrical dysfunction of the heart, often leading to heart failure-related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. We showed here an increase in oxidative stress levels in the hearts of mice carrying LMNA mutation, associated with a decrease of the key cellular antioxidant glutathione (GHS). Oral administration of N-acetyl cysteine, a GHS precursor, led to a marked improvement of GHS content, a decrease in oxidative stress markers including protein carbonyls and an improvement of left ventricular structure and function in a model of LMNA cardiomyopathy. Collectively, our novel results provide therapeutic insights into LMNA cardiomyopathy.
Genetic and epigenetic changes associated with polygenic left ventricular hypertrophy
- Authors: Prestes, Priscilla
- Date: 2021
- Type: Text , Thesis , PhD
- Full Text:
- Description: Cardiac hypertrophy (CH) is the thickening of heart muscles reducing functionality and increasing risk of cardiac disease. Commonly, pathological CH is presented as left ventricular hypertrophy (LVH) and genetic factors are known to be involved but their contribution is still poorly understood. I used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of LVH, and its control strain, the normal heart rat (NHR) to investigate genetic and epigenetic contributions to LVH independent of high blood pressure. To address this study, I used a systematic approach. Firstly, I sequenced the whole genome of HHR and NHR to identify genes related to LVH, focusing on quantitative trait locus Cm22. I found the gene for tripartite motif-containing 55 (Trim55) was significantly downregulated and also presented decreased protein expression with the presence of one exonic missense mutation that altered the protein structure. Interestingly, Trim55 mRNA expression was reduced in idiopathic dilated cardiomyopathic hearts. Secondly, I selected 42 genes previously described in monogenic forms of human cardiomyopathies and studied DNA variants, mRNA and micro RNA (miRNA) expression to determine their involvement in this polygenic model of LVH at five ages. This comprehensive approach identified the differential expression of 29 genes in at least one age group and two miRNAs in validated miRNA-mRNA interactions. These two miRNAs have binding sites for five of the genes studied. Lastly, I found circular RNA (circRNA) Hrcr was upregulated in the hypertrophic heart. I then silenced Hrcr expression in human primary cardiomyocytes to investigate its miRNA downstream targets and elucidate possible regulatory mechanisms. I described four miRNAs (miR-1-3p, miR-330, miR-27a-5p, miR-299-5p) as novel targets for HRCR and predicted 359 mRNA targets in the circRNA-miRNA-mRNA regulatory axis. In silico analysis identified 206 enriched gene ontology based on the predicted mRNA target list, including cardiomyocyte differentiation and ventricular cardiac muscle cell differentiation. The findings in this thesis suggest that 1) Trim55 is a novel functional candidate gene for polygenic LVH; 2) genes implicated in monogenic forms of cardiomyopathy may be involved in this condition and 3) circRNA expression is associated with changes in hypertrophic hearts and deserve further attention.
- Description: Doctor of Philosophy
- Authors: Prestes, Priscilla
- Date: 2021
- Type: Text , Thesis , PhD
- Full Text:
- Description: Cardiac hypertrophy (CH) is the thickening of heart muscles reducing functionality and increasing risk of cardiac disease. Commonly, pathological CH is presented as left ventricular hypertrophy (LVH) and genetic factors are known to be involved but their contribution is still poorly understood. I used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of LVH, and its control strain, the normal heart rat (NHR) to investigate genetic and epigenetic contributions to LVH independent of high blood pressure. To address this study, I used a systematic approach. Firstly, I sequenced the whole genome of HHR and NHR to identify genes related to LVH, focusing on quantitative trait locus Cm22. I found the gene for tripartite motif-containing 55 (Trim55) was significantly downregulated and also presented decreased protein expression with the presence of one exonic missense mutation that altered the protein structure. Interestingly, Trim55 mRNA expression was reduced in idiopathic dilated cardiomyopathic hearts. Secondly, I selected 42 genes previously described in monogenic forms of human cardiomyopathies and studied DNA variants, mRNA and micro RNA (miRNA) expression to determine their involvement in this polygenic model of LVH at five ages. This comprehensive approach identified the differential expression of 29 genes in at least one age group and two miRNAs in validated miRNA-mRNA interactions. These two miRNAs have binding sites for five of the genes studied. Lastly, I found circular RNA (circRNA) Hrcr was upregulated in the hypertrophic heart. I then silenced Hrcr expression in human primary cardiomyocytes to investigate its miRNA downstream targets and elucidate possible regulatory mechanisms. I described four miRNAs (miR-1-3p, miR-330, miR-27a-5p, miR-299-5p) as novel targets for HRCR and predicted 359 mRNA targets in the circRNA-miRNA-mRNA regulatory axis. In silico analysis identified 206 enriched gene ontology based on the predicted mRNA target list, including cardiomyocyte differentiation and ventricular cardiac muscle cell differentiation. The findings in this thesis suggest that 1) Trim55 is a novel functional candidate gene for polygenic LVH; 2) genes implicated in monogenic forms of cardiomyopathy may be involved in this condition and 3) circRNA expression is associated with changes in hypertrophic hearts and deserve further attention.
- Description: Doctor of Philosophy
- «
- ‹
- 1
- ›
- »