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Early molecular events in the development of the diabetic cardiomyopathy
H Mönkemann1, A S De Vriese, H J Blom
1Department of Radiology, University of Bonn, Germany.
Unlabelled:
Oxidative damage to DNA has been well documented in cardiac cells isolated from diabetic patients and rats with streptozotocin-induced diabetes mellitus (DM). This study evaluates possible molecular mechanisms for early events in the development of DM-induced cardiomyopathy.
Methods:
To analyze the mechanism of overexpression of p21(WAF1/CIP1) and inhibition of cyclin D(1) expression in cardiomyocytes of diabetic rats we examined the methylation status of these genes by MS-PCR and assessed the possibility of epigenetic control of their expression.
Results:
We found that the steady-state expression of both genes is influenced by their methylation status, as an epigenetic event, of their 5'-flanking regions upon development of diabetes.
Conclusions:
Oxidative damage contributes to the development of cardiomyopathy via p53-dependent activation of cardiac cell death. This pathway includes de novomethylation of the P53-inducible p21(WAF1/CIP1)-gene encoding a protein which binds to and inhibits a broad range of cyclin-cyclin-dependent kinase complexes.
Insights
Diabetes mellitus (DM) causes oxidative damage in the heart. Epigenetic changes, specifically DNA methylation, influence gene expression, leading to diabetic cardiomyopathy via p53-dependent cell death.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Epigenetics
Background:
- Oxidative DNA damage is evident in cardiac cells of diabetic patients and rats.
- Diabetic cardiomyopathy is a significant complication of diabetes mellitus.
Purpose of the Study:
- To investigate the molecular mechanisms underlying early diabetic cardiomyopathy.
- To examine the epigenetic regulation of p21(WAF1/CIP1) and cyclin D(1) in diabetic rat cardiomyocytes.
Main Methods:
- Methylation-specific PCR (MS-PCR) was used to analyze gene methylation status.
- Gene expression levels of p21(WAF1/CIP1) and cyclin D(1) were assessed.
- Epigenetic control mechanisms were evaluated.
Main Results:
- Diabetes mellitus influences the expression of p21(WAF1/CIP1) and cyclin D(1).
- The methylation status of the 5'-flanking regions of these genes is altered in diabetic conditions.
- Epigenetic modifications correlate with changes in gene expression.
Conclusions:
- Oxidative damage contributes to diabetic cardiomyopathy through p53-dependent cardiac cell death.
- De novo demethylation of the p53-inducible p21(WAF1/CIP1) gene is implicated in this pathway.
- Inhibition of cyclin-cyclin-dependent kinase complexes by p21(WAF1/CIP1) plays a role in diabetic cardiomyopathy.