Abstract 12010: Physiological Overexpression of PGC-1alpha Preserves Mitochondrial Function and Reduces Fibrosis but Does Not Prevent Cardiac Dysfunction Following Pressure Overload Hypertrophy
Peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1α) is an inducible integrator of transcriptional circuits that regulate mitochondrial biogenesis and function. In physiological cardiac hypertrophy, PGC-1α is activated and mitochondrial function is maintained or enhanced. Conversely, during pathological hypertrophy there is down regulation of PGC-1α, which suggests that decreased expression of the PGC-1α /PPARα transcriptional cascade could be an important molecular basis for energy starvation of the failing myocardium. Therefore, to determine if PGC-1α overexpression could prevent the progression to heart failure in a model of pressure overload hypertrophy (POH), we examined human PGC-1α BAC transgenic (TG) mice following 4wk of transverse aortic constriction (TAC) (n=6 per group). In vivo cardiac contractile function was measured by echocardiography and mitochondrial respirations using palmitoyl-carnitine (PC) were measured in saponin-permeabilized cardiac fibers. PGC-1α protein and mRNA expressions in the heart were increased by 40% and 2-fold respectively in TG sham mice, and were maintained following TAC. Heart weight to body weight ratios were equivalently increased in both control and TG mice following TAC. mRNA expression of the FAO genes FATP-1 and HADHα and the OXPHOS gene Cox5b was reduced in control but not in TG mice following TAC. MCAD expression was increased in TG sham and was preserved in TG TAC mice. State 3 mitochondrial respirations (11.82±0.7 vs. 7.39±0.34 nmol/min/mg, p<0.05) were reduced in control mice after TAC, relative to sham, but were preserved in TG TAC vs. sham (10.90±0.76 vs. 10.32±0.6, p<0.05). ATP production was reduced by 43% in control TAC mice but was also maintained in TG mice after TAC. Cardiac fibrosis was 50% decreased in TG TAC when compared to control TAC mice. However, ejection fraction and fractional shortening were reduced in both TAC groups relative to sham, consistent with decreased contractile function. Thus, PGC-1α overexpression during pressure overload maintains the expression levels of fatty acid oxidation genes, reduces fibrosis and maintains mitochondrial function, but is not sufficient to prevent POH-induced cardiac contractile dysfunction.
- © 2011 by American Heart Association, Inc.