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

Abstract

Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) is a powerful regulator of mitochondrial biology and metabolism. PGC-1 alpha and numerous genes regulated by PGC-1 alpha are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1 alpha 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 alpha 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-1a and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1 alpha can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1 alpha serves a cardioprotective function and suggest that repression of PGC-1 alpha significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1 alpha activity may have therapeutic potential in the treatment of heart failure.