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:
- 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.
- 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.
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.
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