Changes in PPAR gene expression and myocardial tolerance to ischaemia: relevance to pleiotropic effects of statins

Abstract

Peroxisome proliferator-activated receptors (PPAR), which are key transcriptional regulators of lipid metabolism and energy production, have been suggested to play an important role in myocardial ischaemia-reperfusion (I/R) injury. Their role in cardioprotection, however, is not yet fully elucidated. Statins have shown beneficial effects on I/R damage beyond lipid lowering, and some of their cardioprotective cholesterol-independent effects may be related to the regulation of PPAR. To clarify this issue, we explored a potential link between a response to I/R and changes in cardiac PPARalpha protein and gene expression in simvastatin-treated normocholesterolaemic rats. After 5 days of treatment with simvastatin (10 mg/kg per day, p.o.), Langendorff-perfused hearts were subjected to 30 min regional ischaemia (occlusion of the left anterior descending coronary artery) or global ischaemia and 2 h reperfusion for the evaluation of the infarct size (triphenyltetrazolium chloride and planimetry; as percentage of risk area), ischaemic arrhythmias, and postischaemic contractile recovery. Baseline PPARalpha mRNA and protein levels were increased by 3-fold and 2-fold, respectively, in simvastatin-treated hearts compared with the untreated controls. Simvastatin-treated hearts exhibited smaller size of infarction (11.5% +/- 0.4% vs. 33.7% +/- 4% in controls; p < 0.01), improved postischaemic contractile recovery, and lower severity of arrhythmias during ischaemia and early reperfusion. Enhanced resistance to I/R injury was associated with preservation of mRNA and protein levels of PPARalpha in contrast to their marked downregulation in controls. In conclusion, statin-induced changes in the expression of PPARalpha may contribute to attenuation of myocardial I/R injury and thus suggest the involvement of cardioprotective mechanisms independent of inhibition of HMG-CoA reductase.