Inactivation of peroxisome proliferator-activated receptor isoforms alpha, beta/delta, and gamma mediate distinct facets of hypertrophic transformation of adult cardiac myocytes.

Inactivation of peroxisome proliferator-activated receptor (PPARs) isoforms alpha, beta/delta, and gamma mediate distinct facets of hypertrophic transformation of adult cardiac myocytes. PPARs are ligand-activated transcription factors that modulate the transcriptional regulation of fatty acid metabolism and the hypertrophic response in neonatal cardiac myocytes. The purpose of this study was to determine the role of PPAR isoforms in the morphologic and metabolic phenotype transformation of adult cardiac myocytes in culture, which, in medium containing 20% fetal calf serum, undergo hypertrophy-like cell growth associated with downregulation of regulatory proteins of fatty acid metabolism. Expression and DNA-binding activity of PPARalpha, PPARbeta/delta, and PPARgamma rapidly decreased after cell isolation and remained persistently reduced during the 14-day culture period. Cells progressively increased in size and developed both re-expression of atrial natriuretic factor and downregulation of regulatory proteins of fatty acid metabolism. Supplementation of the medium with fatty acid (oleate 0.25 mM/palmitate 0.25 mM) prevented inactivation of PPARs and downregulation of metabolic genes. Furthermore, cell size and markers of hypertrophy were markedly reduced. Selective activation of either PPARalpha or PPARbeta/delta completely restored expression of regulatory genes of fatty acid metabolism but did not influence cardiac myocyte size and markers of hypertrophy. Conversely, activation of PPARgamma prevented cardiomyocyte hypertrophy but had no effect on fatty acid metabolism. The results indicate that PPAR activity markedly influences hypertrophic transformation of adult rat cardiac myocytes. Inactivation of PPARalpha and PPARbeta/delta accounts for downregulation of the fatty acid oxidation pathway, whereas inactivation of PPARgamma enables development of hypertrophy.