PPAR transcriptional activator complex polymorphisms and the promise of individualized therapy for heart failure

The PPAR gene pathway consists of interrelated genes that encode transcription factors, enzymes, and downstream targets which coordinately act to regulate cellular processes central to glucose and lipid metabolism. The pathway includes the PPAR genes themselves, other class II nuclear hormone receptor transcription factors within the PPAR family, PPAR co-activators, PPAR co-repressors, and downstream metabolic gene targets. This review focuses on the transcription factors that comprise the PPAR transcriptional activator complex--the PPARs (PPARalpha, PPARbeta, or PPARgamma), PPAR heterodimeric partners, such as RXRalpha, and PPAR co-activators, such as PPARgamma coactivator 1alpha (PGC-1alpha) and the estrogen-related receptors (ERRalpha, ERRbeta, and ERRgamma). These transcription factors have been implicated in the development of myocardial hypertrophy and dilated cardiomyopathy as well as response to myocardial ischemia/infarction and, by association, ischemic cardiomyopathy. Human expression studies and animal data are presented as the background for a discussion of the emerging field of pharmacogenetics as it applies to these genes and the consequent implications for the individualization of therapy for patients with heart failure.