Activation of genes inducing cell-cycle arrest and of increased DNA repair in the hearts of rats with early streptozotocin-induced diabetes mellitus.

Background: Oxidative stress was proposed as a critical factor in diabetic complications. The etiology of cell degeneration in diabetes mellitus (DM)-induced cardiomyopathy is unclear. The transition between apoptotic degeneration and cell proliferation under stress conditions is regulated at cell-cycle checkpoints. This study was aimed at elucidating the role of a potent cellular stress-response system of the p53-dependent checkpoint genes, i.e. P21WAF1/CIP1 and 14-3-3 sigma, in the heart in diabetes.

Material/methods: Target gene expression levels were analyzed ex vivo in cardiomyocytes of streptozotocin-induced rats by Western blots and two-dimensional immunoblots. The levels of DNA damage/repair in 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 p21WAF1/CIP1 were found in cardiomyocytes of the controls, high expression rates of all three genes were observed in the DM group. Individual levels of DNA breakage were significantly lower in diabetic than in non-diabetic cardiomyocytes.

Conclusions: We propose a dual role for cell-cycle regulation under diabetic conditions: the expressions of both p21WAF1/CIP1 and 14-3-3 sigma genes, activated via p53 function, trigger cell-cycle arrest and DNA repair, preventing replication of mutated DNA and increasing stress resistance of heart tissue at least in early diabetes. However, the double cell-cycle arrest ultimately inhibits the replication of cells, which consequently accumulate in the G1 and G2 phases; this could lead to retarded proliferative activity and tissue degeneration in diabetic myocardium in later diabetes.