PGC-1 alpha regulates expression of myocardial mitochondrial antioxidants and myocardial oxidative stress after chronic systolic overload.
Mitochondria are a principal site for generation of reactive oxygen species (ROS) in the heart. Peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1 alpha) plays an important role in regulating mitochondrial biogenesis and myocardial metabolism, but whether PGC-1 alpha can simultaneously upregulate myocardial mitochondrial antioxidants has not been studied. In the present study, we examined the effect of PGC-1 alpha deficiency (PGC-1 alpha(-/-)) 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-1 alpha(-/-) 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-1 alpha(-/-) 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/dt(max) than did wild-type hearts. SOD mimetic MnTMPyP treatment (6 mg/kg/day) significantly attenuated TAC-induced LV hypertrophy and dysfunction in PGC-1 alpha(-/-) mice. These data indicate that PGC-1 alpha 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.
Lu
Zhongbing
Z
Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Xu
Xin
X
Hu
Xinli
X
Fassett
John
J
Zhu
Guangshuo
G
Tao
Yi
Y
Li
Jingxin
J
Huang
Yimin
Y
Zhang
Ping
P
Zhao
Baolu
B
Chen
Yingjie
Y
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009603:Nitroso Compounds / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013599:Systole / Q000187:drug effects; D013879:Thioredoxins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
C443112:3-nitrosotyrosine; D000447:Aldehydes; D000975:Antioxidants; D009603:Nitroso Compounds; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors; D014443:Tyrosine; D013879:Thioredoxins; D013482:Superoxide Dismutase; C027576:4-hydroxy-2-nonenal
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