Cardioprotective effect of chronic hyperglycemia: effect on hypoxia-induced apoptosis and necrosis

It is generally accepted that mild forms of diabetes render the heart resis tant to an ischemic insult. Because myocytes incubated chronically in mediu m containing high concentrations of glucose (25 mM) develop into a diabetes -like phenotype, we tested the hypothesis that high-glucose treatment dimin ishes hypoxia-induced injury. In support of this hypothesis, we found that cardiomyocytes incubated for 3 days with medium containing 25 mM glucose sh owed less hypoxia-induced apoptosis and necrosis than cells exposed to medi um containing 5 mM glucose (control). Indeed, whereas 27% of control cells became necrotic after 1 h of chemical hypoxia with 10 mM deoxyglucose and 5 mM amobarbital (Amytal), only 11% of the glucose-treated cells became necr otic. Similarly, glucose treatment reduced the extent of apoptosis from 32% to 12%. This beneficial effect of glucose treatment was associated with a 40% reduction in the Ca2+ content of the hypoxic cell. Glucose treatment al so mediated an upregulation of the cardioprotective factor Bcl-2 but did no t affect the cellular content of the proapoptotic factors Bax and Bad. None theless, the phosphorylation state of Bad was shifted in favor of its inact ive, phosphorylated form after high-glucose treatment. These data suggest t hat glucose treatment renders the cardiomyocyte resistant to hypoxia-induce d apoptosis and necrosis by preventing the accumulation of Ca2+ during hypo xia, promoting the upregulation of Bcl-2, and enhancing the inactivation of Bad.