Dataset Information

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

ACCESS DATA

Publications

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

Hobson Michael J MJ Hake Paul W PW O'Connor Michael M Schulte Christine C Moore Victoria V James Jeanne M JM Piraino Giovanna G Zingarelli Basilia B

Shock (Augusta, Ga.) 20140101 1

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, using a model of conditional cardiomyocyte-specific deletion of PPARγ in vivo. In mice, α-myosin heavy chain-restri ...[more]

PMID: 24089001

Similar Datasets

Project description:ObjectiveCardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARgamma ligands could attenuate cardiac fibrosis.Research design and methodsWild-type cardiomyocyte- and macrophage-specific PPARgamma(-/-) mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPARgamma ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPARgamma in cardiac fibrosis.ResultsCardiomyocyte-specific PPARgamma(-/-) mice (cPPARgamma(-/-)) developed spontaneous cardiac hypertrophy with increased ventricular osteopontin expression and macrophage content, which were exacerbated by AngII infusion. Pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation, and osteopontin expression in both wild-type and cPPARgamma(-/-) mice but induced hypertrophy in a PPARgamma-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPARgamma-independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPARgamma ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPARgamma(-/-) mice.ConclusionsWe arrived at the following conclusions: 1) both cardiomyocyte-specific PPARgamma deficiency and activation promote cardiac hypertrophy, 2) both cardiomyocyte and monocyte PPARgamma regulate cardiac macrophage infiltration, 3) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4) macrophage PPARgamma activation prevents myocardial macrophage accumulation, and 5) PPARgamma ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets