PGC-1α regulates expression of myocardial mitochondrial antioxidants and myocardial oxidative stress after chronic systolic overload

Zhongbing Lu, Xin Xu, Xinli Hu, John Fassett, Guangshuo Zhu, Yi Tao, Jingxin Li, Yimin Huang, Ping Zhang, Baolu Zhao, Yingjie Chen

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136 Scopus citations

Abstract

Mitochondria are a principal site for generation of reactive oxygen species (ROS) in the heart. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) plays an important role in regulating mitochondrial biogenesis and myocardial metabolism, but whether PGC-1α can simultaneously upregulate myocardial mitochondrial antioxidants has not been studied. In the present study, we examined the effect of PGC-1α deficiency (PGC-1α-/-) on oxidative stress and expression of a group of mitochondrial antioxidants in normal hearts and in hearts exposed to chronic systolic pressure overload produced by transverse aortic constriction (TAC). We found that PGC-1α-/- caused moderate but significant decreases of myocardial mitochondrial antioxidant enzymes such as SOD2, and thioredoxin (Trx2), but had no effect on expression of myocardial oxidative stress markers and left ventricular (LV) function under basal conditions. However, in response to TAC for 6 weeks, PGC-1α-/- mice showed greater increases of myocardial oxidative stress markers 3'-nitrotyrosine and 4-hydroxynonenal, more severe LV hypertrophy and dilatation, pulmonary congestion, and a greater reduction of LV fractional shortening and dP/dtmax than did wild-type hearts. SOD mimetic MnTMPyP treatment (6mg/kg/day) significantly attenuated TAC-induced LV hypertrophy and dysfunction in PGC-1α-/- mice. These data indicate that PGC-1α plays an important role in regulating expression of myocardial mitochondrial antioxidants SOD2 and Trx2 and in protecting hearts against TAC-induced myocardial oxidative stress, hypertrophy, and dysfunction.

Original languageEnglish (US)
Pages (from-to)1011-1022
Number of pages12
JournalAntioxidants and Redox Signaling
Volume13
Issue number7
DOIs
StatePublished - Oct 1 2010

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