Glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in rat adult cardiomyocytes

Several studies support the concept of a diabetic cardiomyopathy in the abs ence of discernible coronary artery disease, although its mechanism remains poorly understood. We investigated the role of glucose and palmitic acid o n cardiomyocyte apoptosis and on the organization of the contractile appara tus. Exposure of adult rat cardiomyocytes for 18 h to palmitic acid (0.25 a nd 0.5 mmol/l) resulted in a significant increase of apoptotic cells, where as increasing glucose concentration to 33.3 mmol/l for up to 8 days had no influence on the apoptosis rate. However, both palmitic acid and elevated g lucose concentration alone or in combination had a dramatic destructive eff ect on the myofibrillar apparatus. The membrane-permeable C-2-ceramide but not the metabolically inactive C-2-dihydroceramide enhanced apoptosis of ca rdiomyocytes by 50%, accompanied by detrimental effects on the myofibrils. The palmitic acid-induced effects were impaired by fumonisin B1, an inhibit or of ceramide synthase. Sphingomyelinase, which activates the catabolic pa thway of ceramide by metabolizing sphingomyeline to ceramide, did not adver sely affect cardiomyocytes. Palmitic acid-induced apoptosis was accompanied by release of cytochrome c from the mitochondria. Aminoguanidine did not p revent glucose-induced myofibrillar degeneration, suggesting that formation of nitric oxide and/or advanced glycation end products play no major role. Taken together, these results suggest that in adult rat cardiac cells, pal mitic acid induces apoptosis via de novo ceramide formation and activation of the apoptotic mitochondrial pathway. Conversely, glucose has no influenc e on adult cardiomyocyte apoptosis. However, both cell nutrients promote de generation of myofibrils. Thus, gluco- and lipotoxicity may play a central role in the development of diabetic cardiomyopathy.