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 (6 mg/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. Antioxid. Redox Signal. 13, 1011–1022.
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References
1.
AranyZ, HeH, LinJ, HoyerK, HandschinC, TokaO, AhmadF, MatsuiT, ChinS, WuPH, RybkinII, SheltonJM, ManieriM, CintiS, SchoenFJ, Bassel–DubyR, RosenzweigA, IngwallJS, SpiegelmanBM. Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab, 1:259–271. 2005.
2.
AranyZ, NovikovM, ChinS, MaY, RosenzweigA, SpiegelmanBM. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha. Proc Natl Acad Sci USA, 103:10086–10091. 2006.
3.
BalabanRS, NemotoS, FinkelT. Mitochondria, oxidants, and aging. Cell, 120:483–495. 2005.
4.
ConradM, JakupogluC, MorenoSG, LipplS, BanjacA, SchneiderM, BeckH, HatzopoulosAK, JustU, SinowatzF, SchmahlW, ChienKR, WurstW, BornkammGW, BrielmeierM. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol Cell Biol, 24:9414–9423. 2004.
5.
FinckBN, KellyDP. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) regulatory cascade in cardiac physiology and disease. Circulation, 115:2540–2548. 2007.
6.
FinckBN, KellyDP. PGC-1 coactivators: Inducible regulators of energy metabolism in health and disease. J Clin Invest, 116:615–622. 2006.
GuellichA, DamyT, LecarpentierY, ContiM, ClaesV, SamuelJL, QuillardJ, HebertJL, PineauT, CoiraultC. Role of oxidative stress in cardiac dysfunction of PPARalpha-/- mice. Am J Physiol Heart Circ Physiol, 293:H93–H102. 2007.
9.
HuP, ZhangD, SwensonL, ChakrabartiG, AbelED, LitwinSE. Minimally invasive aortic banding in mice: Effects of altered cardiomyocyte insulin signaling during pressure overload. Am J Physiol Heart Circ Physiol, 285:H1261–H1269. 2003.
10.
HuX, XuX, HuangY, FassettJ, FlaggTP, ZhangY, NicholsCG, BacheRJ, ChenY. Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload. Circ Res, 103:1009–1017. 2008.
11.
HussJM, ImahashiK, DufourCR, WeinheimerCJ, CourtoisM, KovacsA, GiguereV, MurphyE, KellyDP. The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell Metab, 6:25–37. 2007.
12.
IdeT, TsutsuiH, KinugawaS, UtsumiH, KangD, HattoriN, UchidaK, ArimuraK, EgashiraK, TakeshitaA. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res, 85:357–363. 1999.
KukidomeD, NishikawaT, SonodaK, ImotoK, FujisawaK, YanoM, MotoshimaH, TaguchiT, MatsumuraT, ArakiE. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes, 55:120–127. 2006.
15.
LehmanJJ, BoudinaS, BankeNH, SambandamN, HanX, YoungDM, LeoneTC, GrossRW, LewandowskiED, AbelED, KellyDP. The transcriptional coactivator PGC-1alpha is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis. Am J Physiol Heart Circ Physiol, 295:H185–H196. 2008.
LochT, VakhrushevaO, PiotrowskaI, ZiolkowskiW, EbeltH, BraunT, BoberE. Different extent of cardiac malfunction and resistance to oxidative stress in heterozygous and homozygous manganese-dependent superoxide dismutase-mutant mice. Cardiovasc Res, 82:448–457. 2009.
18.
LuZ, FassettJ, XuX, HuX, ZhuG, FrenchJ, ZhangP, SchnermannJ, BacheRJ, ChenY. Adenosine A3 receptor deficiency exerts unanticipated protective effects on the pressure-overloaded left ventricle. Circulation, 118:1713–1721. 2008.
19.
LuZ, XuX, HuX, LeeS, TraverseJH, ZhuG, FassettJ, TaoY, ZhangP, DosRC, PritzkerM, HallJL, GarryDJ, ChenY. Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation, 121:1474–1483. 2010.
20.
LuZ, XuX, HuX, ZhuG, ZhangP, van DeelED, FrenchJP, FassettJT, OuryTD, BacheRJ, ChenY. Extracellular superoxide dismutase deficiency exacerbates pressure overload-induced left ventricular hypertrophy and dysfunction. Hypertension, 51:19–25. 2008.
21.
MatsushimaS, IdeT, YamatoM, MatsusakaH, HattoriF, IkeuchiM, KubotaT, SunagawaK, HasegawaY, KuriharaT, OikawaS, KinugawaS, TsutsuiH. Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation, 113:1779–1786. 2006.
NonnL, WilliamsRR, EricksonRP, PowisG. The absence of mitochondrial thioredoxin 2 causes massive apoptosis, exencephaly, and early embryonic lethality in homozygous mice. Mol Cell Biol, 23:916–922. 2003.
24.
OkiyamaW, TanakaN, NakajimaT, TanakaE, KiyosawaK, GonzalezFJ, AoyamaT. Polyenephosphatidylcholine prevents alcoholic liver disease in PPARalpha-null mice through attenuation of increases in oxidative stress. J Hepatol, 50:1236–1246. 2009.
25.
RangwalaSM, LiX, LindsleyL, WangX, ShaughnessyS, DanielsTG, SzustakowskiJ, NirmalaNR, WuZ, StevensonSC. Estrogen-related receptor alpha is essential for the expression of antioxidant protection genes and mitochondrial function. Biochem Biophys Res Commun, 357:231–236. 2007.
26.
RockmanHA, RossRS, HarrisAN, KnowltonKU, SteinhelperME, FieldLJ, RossJJr, ChienKR. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc Natl Acad Sci USA, 88:8277–8281. 1991.
27.
SanoM, WangSC, ShiraiM, ScagliaF, XieM, SakaiS, TanakaT, KulkarniPA, BargerPM, YoukerKA, TaffetGE, HamamoriY, MichaelLH, CraigenWJ, SchneiderMD. Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. EMBO J, 23:3559–3569. 2004.
28.
SmeetsPJ, TeunissenBE, WillemsenPH, van NieuwenhovenFA, BrounsAE, JanssenBJ, CleutjensJP, StaelsB, van dV, vanBM. Cardiac hypertrophy is enhanced in PPAR alpha-/- mice in response to chronic pressure overload. Cardiovasc Res, 78:79–89. 2008.
29.
St-PierreJ, DroriS, UldryM, SilvaggiJM, RheeJ, JagerS, HandschinC, ZhengK, LinJ, YangW, SimonDK, BachooR, SpiegelmanBM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127:397–408. 2006.
30.
St-PierreJ, LinJ, KraussS, TarrPT, YangR, NewgardCB, SpiegelmanBM. Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells. J Biol Chem, 278:26597–26603. 2003.
31.
TakimotoE, KassDA. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension, 49:241–248. 2007.
32.
ValleI, varez-BarrientosA, ArzaE, LamasS, MonsalveM. PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res, 66:562–573. 2005.
33.
WuZ, PuigserverP, AnderssonU, ZhangC, AdelmantG, MoothaV, TroyA, CintiS, LowellB, ScarpullaRC, SpiegelmanBM. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell, 98:115–124. 1999.
34.
ZhangP, XuX, HuX, van DeelED, ZhuG, ChenY. Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res, 100:1089–1098. 2007.
