Peroxisome Proliferator-activated Receptor {delta} is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2010 Jan 16

PMID 20075336

Citations 57

Authors

Peiyong Wang

Jian Liu

Yuquan Li

Sijie Wu

Jinwen Luo

Huan Yang

Ramasamy Subbiah

John Chatham

Olga Zhelyabovska

Qinglin Yang

Affiliations

Soon will be listed here.

Abstract

Rationale: Peroxisome proliferator-activated receptors (PPARs) (alpha, gamma, and delta/beta) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPARdelta deficiency in mice leads to depressed myocardial fatty acid oxidation, bioenergetics, and premature death with lipotoxic cardiomyopathy.

Objective: To explore the essential role of PPARdelta in the adult heart.

Methods And Results: We investigated the consequences of inducible short-term PPARdelta knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPARdelta knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase and manganese superoxide dismutase, leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPARgamma coactivator-1 were substantially decreased in the short-term PPARdelta deficient heart, concomitant with a decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPARdelta knockout hearts. Consequently, PPARdelta deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy.

Conclusions: PPARdelta is an essential regulator of cardiac mitochondrial protection and biogenesis and PPARdelta activation can be a potential therapeutic target for cardiac disorders.

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