Activation of Peroxisome Proliferator–Activated Receptor-α Protects the Heart From Ischemia/Reperfusion Injury

Abstract

Background-Peroxisome proliferator-activated receptor-␣ (PPAR-␣) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR-␣ in acute ischemia/reperfusion myocardial injury remains unclear. Methods and Results-The coronary arteries of male mice were ligated for 30 minutes. After reperfusion for 24 hours, ischemic and infarct sizes were determined. A highly selective and potent PPAR-␣ agonist, GW7647, was administered by mouth for 2 days, and the third dose was given 1 hour before ischemia. GW7647 at 1 and 3 mg · kg Ϫ1 · d Ϫ1 reduced infarct size by 28% and 35%, respectively (PϽ0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-␣-null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR-␣ and FAO enzyme genes, decreased myocardial FAO enzyme activity and in vivo cardiac fat oxidation, and increased serum levels of free fatty acids. All of these changes were reversed by GW7647. Moreover, GW7647 attenuated ischemia/reperfusion-induced release of multiple proinflammatory cytokines and inhibited neutrophil accumulation and myocardial expression of matrix metalloproteinases-9 and -2. Furthermore, GW7647 inhibited nuclear factor-B activation in the heart, accompanied by enhanced levels of inhibitor-B␣. Conclusions-Activation of PPAR-␣ protected the heart from reperfusion injury. This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. This novel effect of the PPAR-␣ agonist could provide an added benefit to patients treated with PPAR-␣ activators for dyslipidemia.

The role of PPAR in myocardial response to ischemia in normal and diseased heart

“…In this context, treatment with PPAR-α selective and potent agonist GW7647, that reversed I/R-induced down-regulation of PPAR-α and its target genes, attenuated myocardial contractile dysfunction and reduced the size of infarction (Yue et al 2003). Similar cardioprotective effects, in conjunction with the metabolic effects, were observed in a rat ex vivo model of 30-min ischemia/2-h reperfusion after treatment with PPAR-α agonist clofibrate (Tian et al 2006).…”

“…On the other hand, other studies indicated that targeted deletion of PPAR-α resulted in increased serum levels of free FA and a larger size of infarction in mice subjected to ischemic challenge (Yue et al 2003). In acute settings of I/R, decrease of PPAR-α and corresponding metabolic effects were observed in a rat ex vivo model of 30-min ischemia/2-h reperfusion (Tian et al 2006) and in the in vivo mice.…”

“…In acute settings of I/R, decrease of PPAR-α and corresponding metabolic effects were observed in a rat ex vivo model of 30-min ischemia/2-h reperfusion (Tian et al 2006) and in the in vivo mice. In these models, reversal of down-regulation of PPAR-α and its target genes responsible for the metabolic fuel shifts (decreased FAO and increased glucose oxidation) improved postischemic myocardial contractile recovery and reduced the size of infarction (Yue et al 2003). In line, in our study in the isolated rat heart, 30-min global ischemia significantly decreased mRNA and protein levels of PPAR-α and their further decline observed following 2-h reperfusion was accompanied by the development of irreversible myocardial injury (Ravingerová et al 2009).…”

“…Activation of PPAR-α with synthetic ligands has been shown to be cardioprotective in a setting of I/R as manifested by a reduced infarct size and improved postischemic recovery of contractile function in different in vivo and ex vivo models of I/R (Wayman et al 2002;Yue et al 2003;Tian et al 2006). In this context, treatment with PPAR-α selective and potent agonist GW7647, that reversed I/R-induced down-regulation of PPAR-α and its target genes, attenuated myocardial contractile dysfunction and reduced the size of infarction (Yue et al 2003).…”

“…Nevertheless, it is still a matter of debate whether PPAR activation plays a beneficial or detrimental role in the setting of ischemia/reperfusion (I/R), in particular in pathologically altered myocardium. Conflicting findings have documented both, negative impact of PPAR-α up-regulation on myocardial functional recovery upon I/R (Panagia et al 2005;Sambandam et al 2006), in particular during early reperfusion (Kantor et al 2000), and beneficial effects of PPAR-α and PPAR-γ agonists on I/R damage (Tabernero et al 2002;Wayman et al 2002;Yue et al 2003;Yeh et al 2006). This contradiction is apparently related to the fact that PPAR activation may improve myocardial function via metabolic or other, metabolic-independent, actions.…”