Novel cardioprotective effects of pravastatin in human ventricular cardiomyocytes subjected to hypoxia and reoxygenation: Beneficial effects of statins independent of endothelial cells

Cardioprotective strategies are needed to prevent perioperative myocardial dysfunction in high-risk patients undergoing cardiac surgery. Despite accumulating evidence that statins exert lipid-independent cardio-protective effects, these have been ascribed primarily to improvements in endothelial function and neutrophil-endothelial interaction. The direct effects of statins on cardiomyocytes (independent of endothelial cells) remain unknown. Using a well-characterized model of low-volume hypoxia and reoxygenation, we studied the effects of pravastatin on human ventricular cardiomyocytes. Cardiomyocytes were subjected to 90 min of low-volume hypoxia and 30 min of reoxygenation in the presence and absence of pravastatin (1, 10, and 100 muM) (n = 10 per group). In some experiments, the effects of endothelin (ET) receptor blockade (with bosentan) and nitric oxide synthase (NOS) inhibition (with L-NAME) on pravastatin-mediated cardioprotection were evaluated. Cell survival, NO, and ET-1 production and protein kinase Akt activation were determined. Pravastatin treatment prevented cardiomyocyte cell death following simulated hypoxia and reoxygenation (P < 0.01). This effect was mediated via an increase in NO release, decrease in myocyte ET-1 production/action, and an increase in protein kinase Akt activation. We demonstrate, for the first time, novel protective effects of pravastatin in human ventricular cardiomyocytes independent of endothelial cells or other cell types. Statin therapy may restore ischemic hearts to full functional integrity during cardioplegic arrest through a direct effect on cardiomyocyte survival. (C) 2004 Elsevier Inc. All rights reserved.