What does this research mean for the field?

Activation of PPAR-α by the agonist GW7647 reduces infarct size by 28% and 35% in a mouse model of ischemia/reperfusion injury. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

October 14, 2003

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

Key Result

The PPAR-α agonist GW7647 reduced infarct size by 28% and 35% at doses of 1 and 3 mg/kg/day, respectively, in a mouse model of ischemia/reperfusion injury (P < 0.01).

Structured PICO

Does GW7647 reduce infarct size in male mice subjected to myocardial ischemia/reperfusion injury?

Population

Male mice (CD1, PPAR-α null, and wild-type) subjected to 30 minutes of left anterior descending coronary artery occlusion

Intervention

GW7647 (PPAR-α agonist) administered orally for 2 days, with a third dose 1 hour before ischemia (doses of 0.3, 1, and 3 mg/kg/d)

Comparator

Vehicle

Outcome

Ischemic and infarct sizessurrogate

Activation of PPAR-α with GW7647 protects the heart from ischemia/reperfusion injury through metabolic and anti-inflammatory mechanisms in a mouse model.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Background— Peroxisome proliferator–activated receptor-α (PPAR-α) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR-α 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-α 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 −1 · d −1 reduced infarct size by 28% and 35%, respectively ( P <0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-α–null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR-α 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-κB activation in the heart, accompanied by enhanced levels of inhibitor-κBα. Conclusions— Activation of PPAR-α protected the heart from reperfusion injury. This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. This novel effect of the PPAR-α agonist could provide an added benefit to patients treated with PPAR-α activators for dyslipidemia.