Early molecular events in the development of the diabetic cardiomyopathy

Summary.  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 D₁ 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 novo methylation 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. Received June 29, 2001 Accepted August 6, 2001 Published online August 9, 2002