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Peroxisome proliferator-activated receptor ?/? activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition.

ABSTRACT: Peroxisome proliferator-activated receptor ?/? (PPAR?/?) is an essential transcription factor in myocardial metabolism. This study aims to investigate the effects of PPAR?/? activation in the adult heart on mitochondrial biology and oxidative metabolism under normal and pressure-overload conditions. We have investigated the effects of cardiac constitutively active PPAR?/? in adult mice using a tamoxifen-inducible transgenic approach with Cre-LoxP recombination. The expression of PPAR?/? mRNA and protein in cardiomyocytes of adult mice was substantially increased after short-term induction. In these mice, the cardiac expression of key factors involved in mitochondrial biogenesis, such as PPAR? coactivator-1, endogenous antioxidants Cu/Zn superoxide dismutase, and catalase, fatty acid, and glucose metabolism, such as carnitine palmitoyltransferase Ib, carnitine palmitoyltransferase II, and glucose transporter 4, were upregulated. Subsequently, myocardial oxidative metabolism was elevated concomitant with an increased mitochondrial DNA copy number and an enhanced cardiac performance. Moreover, activation of PPAR?/? in the adult heart improved cardiac function and resisted progression to pathological development in mechanical stress condition. We conclude that PPAR?/? activation in the adult heart will promote cardiac performance along with transcriptional upregulation of mitochondrial biogenesis and defense, as well as oxidative metabolism at basal and pressure-overload conditions.

SUBMITTER: Liu J

PROVIDER: S-EPMC3439134 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor β/δ activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition.

Liu Jian J Wang Peiyong P Luo Jinwen J Huang Yao Y He Lan L Yang Huan H Li Qingbao Q Wu Sijie S Zhelyabovska Olga O Yang Qinglin Q

Hypertension (Dallas, Tex. : 1979) 20110110 2

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is an essential transcription factor in myocardial metabolism. This study aims to investigate the effects of PPARβ/δ activation in the adult heart on mitochondrial biology and oxidative metabolism under normal and pressure-overload conditions. We have investigated the effects of cardiac constitutively active PPARβ/δ in adult mice using a tamoxifen-inducible transgenic approach with Cre-LoxP recombination. The expression of PPARβ/δ mRNA and ...[more]

PMID: 21220704

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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

Peroxisome proliferator-activated receptor ?/? activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition.

Publications

Peroxisome proliferator-activated receptor β/δ activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition.

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