Conditional deletion of cardiomyocyte peroxisome proliferator-activated receptor ? enhances myocardial ischemia-reperfusion injury in mice.

ABSTRACT: The nuclear transcription factor peroxisome proliferator-activated receptor ? (PPAR?) is a key regulator of the inflammatory response to an array of biologic insults. We have previously demonstrated that PPAR? ligands reduce myocardial ischemia-reperfusion injury in rodents. In the current study, we directly determined the role of cardiomyocyte PPAR? in ischemia-reperfusion injury, using a model of conditional cardiomyocyte-specific deletion of PPAR? in vivo. In mice, ?-myosin heavy chain-restricted Cre-mediated PPAR? deficiency was induced by tamoxifen treatment (30 mg/kg intraperitoneally) for 4 days (PPAR? mice), whereas controls included mice treated with the oil diluent vehicle (PPAR? mice). Western blot and histochemical analyses confirmed that expression of PPAR? protein was abolished in cardiomyocytes of mice treated with tamoxifen, but not with vehicle. After tamoxifen or vehicle treatment, animals were subjected to 30-min ligation of the left anterior descending coronary artery followed by 2-h reperfusion. In PPAR? mice, myocardial ischemia and reperfusion induced extensive myocardial damage, which was associated with elevated tissue activity of myeloperoxidase, indicating infiltration of neutrophils, and elevated plasma levels of troponin I when compared with PPAR? mice. Upon echocardiographic analysis, PPAR? mice also demonstrated ventricular dilatation and systolic dysfunction. Plasma levels of the proinflammatory cytokines interleukin 1? and interleukin 6 were higher in PPAR? mice when compared with PPAR? mice. These pathological events in PPAR? mice were associated with enhanced nuclear factor ?B DNA binding in the infarcted hearts. Thus, our data suggest that cardiomyocyte PPAR? is a crucial protective receptor and may prevent reperfusion injury by modulating mechanisms of inflammation.

SUBMITTER: Hobson MJ 

PROVIDER: S-EPMC3911778 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature