Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR - coactivator 1

Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptorcoactivator 1 (PGC-1 ) is a powerful regulator of mitochondrial biology and metabolism. PGC-1 and numerous genes regulated by PGC-1 are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1 repression may contribute to the maladaptive response of the heart to chronic hemodynamic loads. We show here that TAC in mice genetically engineered to lack PGC-1 leads to accelerated cardiac dysfunction, which is accompanied by signs of significant clinical heart failure. Treating cardiac cells in tissue culture with the catecholamine epinephrine leads to repression of PGC-1 and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1 can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1 serves a cardioprotective function and suggest that repression of PGC-1 significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1 activity may have therapeutic potential in the treatment of heart failure.