01 February 2006
Activation of genes inducing cell-cycle arrest and of increased DNA repairin the hearts of rats with early streptozotocin-induced diabetes mellitus.Olga Golubnitschaja, Heike Moenkemann, Daniela B. Trog, Henk J. Blom, An S. De Vriese
Med Sci Monit 2006; 12(2): BR68-74 :: ID: 445233
Background: Background: Oxidative stress was proposed as a critical factorin diabetic complications. The etiology of cell degeneration in diabetes mellitus (DM)-induced cardiomyopathyis unclear. The transition between apoptotic degeneration and cell proliferation under stress conditionsis regulated at cell-cycle checkpoints. This study was aimed at elucidating the role of a potent cellularstress-response system of the p53-dependent checkpoint genes, i.e. P21(WAF1/CIP1) and 14-3-3 sigma, inthe heart in diabetes. Material/Methods: Target gene expression levels were analyzed ex vivo in cardiomyocytesof streptozotocin-induced rats by Western blots and two-dimensional immunoblots. The levels of DNA damage/repairin diabetic cardiomyocytes were evaluated by "comet assay" and compared with a control group. Results:Whereas no detectable expression of 14-3-3 sigma and only traces of both p53 and p21(WAF1/CIP1) werefound in cardiomyocytes of the controls, high expression rates of all three genes were observed in theDM group. Individual levels of DNA breakage were significantly lower in diabetic than in non-diabeticcardiomyocytes. Conclusions: We propose a dual role for cell-cycle regulation under diabetic conditions:the expressions of both p21[sup]WAF1/CIP1[/sup] and 14-3-3 sigma genes, activated via p53 function, trigger cell-cyclearrest and DNA repair, preventing replication of mutated DNA and increasing stress resistance of hearttissue at least in early diabetes. However, the double cell-cycle arrest ultimately inhibits the replicationof cells, which consequently accumulate in the G(1) and G(2) phases; this could lead to retarded proliferativeactivity and tissue degeneration in diabetic myocardium in later diabetes.
Keywords: Cell Cycle - genetics, Cardiomyopathies - pathology, Comet Assay, Cyclin-Dependent Kinase Inhibitor p21 - genetics, DNA Repair - genetics, Diabetes Mellitus, Experimental - pathology, Gene Expression Regulation, Genes, p53, Myocardium - pathology, Myocytes, Cardiac - pathology, Rats, Wistar
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