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

Abstract

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.

FIG. 1.

PGC-1α^−/− significantly exacerbates chronic TAC-induced LV hypertrophy and fibrosis. Chronic TAC caused greater LV hypertrophy (A) and pulmonary congestion (B) in PGC-1α^−/− as compared with wild-type mice. Chronic TAC causes similar degree of LV fibrosis (C, E), but more cardiac myocyte hypertrophy (D, F) in PGC-1α^−/− as compared with wild-type mice. *p < 0.05 compared to the corresponding control; ^#p < 0.05 compared to Wt-TAC.

FIG. 2.

PGC-1α^−/− significantly exacerbates chronic TAC-induced LV dysfunction. PGC-1α^−/− significantly exacerbates chronic moderate TAC-induced decrease of LV fraction shortening (A, B), decrease of LV contractility as demonstrated by the decrease of LV dP/dt_max and LV dP/dt_min (C, D), and increase of myocardial ANP (E, F). *p < 0.05 compared to the corresponding control; ^#p < 0.05 compared to wild type.

FIG. 3.

PGC-1α^−/− significantly attenuated expressions of myocardial SOD2, Prx3, Prx5, Trx2, and TrxR2 Protein or mRNA. PGC-1α^−/− significantly attenuates mRNA contents (C) and protein expressions of myocardial mitochondrial antioxidants SOD2, Prx3, Prx5, Trx2, and TrxR2 under control conditions or after TAC (A, B). Data are normalized to wild-type control mice. *p < 0.05 compared to the corresponding control; ^#p < 0.05 compared to wild type.

FIG. 4.

PGC-1α^−/− has no effect on protein expression of myocardial SOD1, SOD3, and catalase, but significantly exacerbated the TAC-induced increase of LV oxidative stress (A, B). Data are normalized to wild-type control mice. *p < 0.05 compared to the corresponding control; ^#p < 0.05 compared to wild type.

FIG. 5.

Effect of PGC-1α^−/− on expression of myocardial metabolism related transcriptional factors, metabolic enzymes, and citrate synthase activity. PGC-1α^−/− had no effect on myocardial PGC-1β, but significantly attenuated expressions of myocardial ERRα, PPARα, ERRγ, mtTFA, and NRF1 under control conditions or after TAC, which was associated with decrease of myocardial ERRα, PPARα, Cyto C, COX-III, CD36, and MCAD (A–C). PGC-1α^−/− also decreased myocardial citrate synthase activity under control condition and after TAC (D). Data are normalized to wild-type control mice. *p < 0.05 compared to the corresponding control; ^#p < 0.05 compared to wild type.

FIG. 6.

SOD mimetic MnTMPyP significantly attenuated TAC-induced LV hypertrophy, dysfunction, and increase of LV oxidative stress in PGC-1α^−/− mice. SOD mimetic MnTMPyP significantly attenuated TAC-induced LV hypertrophy (A) and LV dysfunction (B–D) in PGC-1α^−/− mice. *p < 0.05 compared to TAC group; MnTMPyP also attenuated TAC induced the decrease of citrate synthase activity (E) and increase of ANP and 3’-NT content (F–I). The potential signaling pathways for the exacerbated LV myocardial oxidative stress and heart failure in PGC-1α^−/− mice are summarized in panel (J). *p < 0.05 compared to the control; ^#p < 0.05 compared to TAC group.