The PGC-1 cascade as a therapeutic target for heart failure

The PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators, together with estrogen related receptors (ERRs), plays a key role in regulating genes involved in myocardial fuel metabolism and cardiac function. Increasing evidence implicates dysregulation of this transcriptional regulatory circuit in the metabolic and functional disturbances that presage heart failure due to common diseases such as hypertension and diabetes. Accordingly, the PGC-1/ERR axis is a plausible candidate therapeutic target for novel therapeutics aimed at reversing the energy metabolic disturbances that contribute to heart failure. This review describes the biologic actions of the PGC-1 and ERR cascade and summarizes the evidence that dysregulation of this transcriptional regulatory circuit contributes to heart failure. Potential strategies to modulate this target pathway are reviewed. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure.”

Research Highlights
► PGC-1 signaling is necessary for a high capacity mitochondrial system in heart.
► PGC-1 and its target, ERR, are downregulated in heart failure.
► The PGC-1/ERR axis is a potential target for novel heart failure therapeutics.