Conditional Deletion of Cardiomyocyte Peroxisome Proliferator-Activated Receptor γ Enhances Myocardial Ischemia-Reperfusion Injury in Mice

Abstract

The nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) is a key regulator of the inflammatory response to an array of biologic insults. We have previously demonstrated that PPARγ ligands reduce myocardial ischemia-reperfusion injury in rodents. In the current study, we directly determined the role of cardiomyocyte PPARγ in ischemia-reperfusion injury, employing a model of conditional cardiomyocyte-specific deletion of PPARγ in vivo. In mice, α-myosin heavy chain-restricted Cre-mediated PPARγ deficiency was induced by tamoxifen treatment (30 mg/kg intraperitoneally) for 4 days (PPARγ−/− mice); whereas controls included mice treated with the oil diluent vehicle (PPARγ+/+ mice). Western blot and histochemical analyses confirmed that expression of PPARγ 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 hrs reperfusion. In PPARγ−/− 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 to PPARγ+/+ mice. PPARγ−/− mice also demonstrated ventricular dilatation and systolic dysfunction upon echocardiographic analysis. Plasma levels of the pro-inflammatory cytokines interleukin-1β and interleukin-6 were higher in PPARγ−/− mice when compared to PPARγ+/+ mice. These pathological events in PPARγ−/− mice were associated with enhanced nuclear factor-κB DNA binding in the infarcted hearts. Thus, our data suggests that cardiomyocyte PPARγ is a crucial protective receptor and may prevent reperfusion injury by modulating mechanisms of inflammation.

The Role of Peroxisome Proliferator-Activated Receptor γ in Mediating Cardioprotection Against Ischemia/Reperfusion Injury

“…The new complex can bind to NF-κB-specific promoter sequences and induce the expression of other inflammatory factors (eg, tumor necrosis factor α, interleukin-1 [IL-1], interleukin-6 [IL-6], intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion molecule-1 [VCAM-1]), which can promote inflammatory responses. 58,75,76…”

Peroxisome Proliferator-Activated Receptors and the Heart: Lessons from the Past and Future Directions

“…Therefore, chronic deactivation of the PPAR- α signaling pathway may upset the normal equilibrium between oxidant production and antioxidant defenses, which can contribute to cardiac damage [ 58 ]. A recent study in PPAR- γ KO mice revealed that PPAR- γ plays a crucial protective role in cardiomyocytes and may prevent myocardial ischemia-reperfusion injury by modulating NF- κ B-associated inflammatory mechanisms in the infarcted myocardium [ 76 ].…”

Peroxisome proliferator-activated receptor (PPAR) gamma in cardiovascular disorders and cardiovascular surgery

“…PPARg, as a potent regulator of FA metabolism and inhibitor of inflammation, plays an important protective role in the heart muscle during ischemia/reperfusion, and TZDs had beneficial effects in animal models. On the other hand, conditional deletion of PPARg in cardiomyocytes significantly augmented the myocardial damage through inflammation [110].…”