Diabetes increases apoptosis and necrosis in both ischemic and nonischemic human myocardium: role of caspases and poly-adenosine diphosphate-ribose polymerase.

OBJECTIVES

Diabetes is an important predictor of morbidity and mortality after cardiac surgery, but the reason is unclear. The aims of these studies, therefore, were to elucidate whether cell death is greater in ischemic and nonischemic diabetic human myocardium than in nondiabetic myocardium and to investigate the underlying mechanism.

METHODS

The right atrial appendages (n = 8 per group) of patients without diabetes and patients with type 1 and 2 diabetes were subjected to 90 minutes of simulated ischemia and 120 minutes reoxygenation. Tissue injury was measured by the release of creatine kinase into the media, and cellular apoptosis and necrosis were assessed in tissue by the terminal transferase deoxyuridine triphosphate nick-end labeling assay and propidium iodide staining. Initiator and effector caspases activations were also measured.

RESULTS

Apoptosis and necrosis were greater in the type 2 and type 1 diabetes groups than in the nondiabetes group both in fresh tissue and after simulated ischemia-reoxygenation. Activation of effector caspases was also higher in the diabetes groups than in the nondiabetes group after simulated ischemia-reoxygenation. Caspase-3 inhibition reduced apoptosis in all study groups without influencing necrosis; however, poly-adenosine diphosphate-ribose polymerase inhibition resulted in a similar reduction in apoptosis and in necrosis in all groups, whereas caspase-2 inhibition did not.

CONCLUSIONS

Diabetes increases both apoptosis and necrosis in human myocardium, both fresh and after being subjected to ischemia-reoxygenation, an effect that is mediated, at least in part, by caspase-3 and poly-adenosine diphosphate-ribose polymerase activation. These results may explain the increased cardiac-related morbidity and mortality associated with cardiac surgery in patients with diabetes.