PPAR Delta activation inhibits angiotensin II induced cardiomyocyte hypertrophy by suppressing intracellular Ca2+ signaling pathway

Abstract

Peroxisome proliferator-activated receptors delta (PPAR delta) is known to be expressed ubiquitously, and the predominant PPAR subtype of cardiac cells. However, relatively less is known regarding the role of PPAR delta in cardiac cells except that PPAR delta ligand treatment protects cardiac hypertrophy by inhibiting NF-B activation. Thus, in the present study, we examined the effect of selective PPAR delta ligand L-165041 on angiotensin II (AngII) induced cardiac hypertrophy and its underlying mechanism using cardiomyocyte. According to our data, L-165041 (10 µM) inhibited AngII-induced [3H] leucine incorporation, induction of the fetal gene atrial natriuretic factor (ANF) and increase of cardiomyocyte size. Previous studies have implicated the activation of focal adhesion kinase (FAK) in the progress of cardiomyocyte hypertrophy. L-165041 pretreatment significantly inhibited AngII-induced intracellular Ca2+ increase and subsequent phosphorylation of FAK. Further experiment using Ca2+ ionophore A23187 confirmed that Ca2+ induced FAK phosphorylation, and this was also blocked by L-165041 pretreatment. In addition, overexpression of PPAR delta using adenovirus significantly inhibited AngII-induced intracellular Ca2+ increase and FAK expression, while PPAR delta siRNA treatment abolished the effect of L-165041. These data indicate that PPAR delta ligand L-165041 inhibits AngII induced cardiac hypertrophy by suppressing intracellular Ca2+/FAK/ERK signaling pathway in a PPAR dependent mechanism.