Cardioprotective effect of chronic hyperglycemia: effect on hypoxia-induced apoptosis and necrosis.
It is generally accepted that mild forms of diabetes render the heart resistant to an ischemic insult. Because myocytes incubated chronically in medium containing high concentrations of glucose (25 mM) develop into a diabetes-like phenotype, we tested the hypothesis that high-glucose treatment diminishes hypoxia-induced injury. In support of this hypothesis, we found that cardiomyocytes incubated for 3 days with medium containing 25 mM glucose showed less hypoxia-induced apoptosis and necrosis than cells exposed to medium 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 necrotic. 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 Ca(2+) content of the hypoxic cell. Glucose treatment also mediated an upregulation of the cardioprotective factor Bcl-2 but did not affect the cellular content of the proapoptotic factors Bax and Bad. Nonetheless, the phosphorylation state of Bad was shifted in favor of its inactive, phosphorylated form after high-glucose treatment. These data suggest that glucose treatment renders the cardiomyocyte resistant to hypoxia-induced apoptosis and necrosis by preventing the accumulation of Ca(2+) during hypoxia, promoting the upregulation of Bcl-2, and enhancing the inactivation of Bad.
Schaffer
S W
SW
Department of Pharmacology, School of Medicine, University of South Alabama, Mobile, Alabama 36688, USA. sschaffe@jaguar1.usouthal.edu
Croft
C B
CB
Solodushko
V
V
D000654:Amobarbital / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002908:Chronic Disease; D003847:Deoxyglucose / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D006943:Hyperglycemia / Q000503:physiopathology*; D000860:Hypoxia / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051025:bcl-Associated Death Protein
C494821:Bad protein, rat; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D003847:Deoxyglucose; D000654:Amobarbital; D005947:Glucose; D002118:Calcium