Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms

Abstract

Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat ventricular myocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured ARVM and whether fenofibrate ameliorated the apoptosis. Aldosterone (1 microM) induced apoptosis by increasing terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei in ARVM. Spironolactone (100 nM), an aldosterone receptor antagonist, but not RU-486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis, indicating that the mineralocorticoid receptor (MR) plays a role. SP-600125 (3 microM)-a selective inhibitor of c-Jun NH(2)-terminal kinase (JNK)-inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress-activated protein kinases, pretreatment with fenofibrate (10 microM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53, and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100 mg*kg body wt(-1)*day(-1)) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly, eplerenone, a selective MR inhibitor, used in chronic pressure-overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Therefore, involvement of JNK MAPK-dependent mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a peroxisome proliferator-activated receptor (PPAR)alpha ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases.

Fenofibrate reduces cardiac remodeling and improves cardiac function in a rat model of severe left ventricle volume overload

“…We observed in our study that fenofibrate significantly reduced the activation of p38 and of AMPK in AR animals. It tended to the same for Erk 1/2, too Fenofibrate has been shown to inhibit stress-activated kinases such as p38 or Jnk in cardiac hypertrophy models in vitro (De Silva et al 2009;Irukayama-Tomobe et al 2004). Similar observations were also made for p38 in the kidneys of hypertensive rats treated with fenofibrate (Hou et al 2010).…”

Lentiviral-mediated p38 MAPK RNAi attenuates aldosterone-induced myocyte apoptosis

“…The cardioprotective effects of SB203580 were shown to be closely associated with its ability to inhibit p38 MAPK. However, another study showed that SB203580 had minimal effects on aldosterone-mediated apoptosis (18). Of the several possible mechanisms which may underly the effects of aldosterone on cardiomyocyte apoptosis, our results suggest a key role for p38 MAPK activation that is known to be associated with cardiomyocyte apoptosis.…”

“…Pharmacological inhibitors of p38 MAPK have been shown to decrease myocyte apoptosis and improve cardiac function and heart failure in vitro and in vivo (16,17). However, a number of studies have demonstrated that SB203580, a p38 MAPK inhibitor, has minimal effects on aldosterone-induced apoptosis (18). Thus, whether the inhibition of p38 MAPK improves aldosterone-mediated apoptosis requires clarification.…”

Role of Pleiotropic Properties of Peroxisome Proliferator‐Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection

“…Furthermore, in a setting of I/R, PPARa activation by its agonist WY-14643 has been implicated in the inhibition of apoptosis through modulation of Bcl-2 family proteins, specifically attributed to the upregulation of Bcl-2 and the concomitant downregulation of Bax [64]. In addition, in vitro studies demonstrated that fenofibrate inhibits JNK MAPK-dependent mitochondrial death pathway in aldosterone-induced apoptosis of adult cardiac myocytes [126].…”