PGC-1α 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 g coactivator 1a (PGC-1a) plays an important role in regulating mitochondrial biogenesis and myocardial metabolism, but whether PGC-1a can simultaneously upregulate myocardial mitochondrial antioxidants has not been studied. In the present study, we examined the effect of PGC-1a deficiency (PGC-1a -=-) 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-1a -=-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-1a -=-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-1a -=-mice. These data indicate that PGC-1a 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.

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

“…One possibility may involve the ability of PGC-1α, under some conditions, to activate genes that are implicated in the response to oxidative stress (34)(35)(36) and thus lead to a reduction of cellular oxidative stress levels. PGC-1α therefore may orchestrate the timely repression of HSPs in response to lower levels of oxidative stress.…”

Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury

“…Therefore, PGC-1␣ can regulate mitochondrial biogenesis. PGC-1␣ loss impairs mitochondrial respiratory function and enhances mitochondrial oxidative stress and apoptotic susceptibility (2,25,40). Haemmerle et al (15) reported that the PGC-1␣ signaling pathway is a potential therapeutic target for the treatment of patients with neutral lipid storage disease.…”

A Role for Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis

“…The selective loss of n-3 PUFA-containing phospholipids could indicate increased lipid peroxidation (35), which previously has been reported in PGC-1␣-deficient hearts in response to pressure overload (36). To explore this possibility, levels of the lipid peroxidation product HNE were determined.…”