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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	De Silva, Deepa S. Wilson, Richard M. Hutchinson, Christoph Ip, Peter C. Garcia, Anthony G. Lancel, Steve Ito, Masa Pimentel, David R. Sam, Flora
Description	Country affiliation: United States Author Affiliation: De Silva DS ( Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.)
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 mgkg 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.
File Format	HTM / HTML
ISSN	03636135
e-ISSN	15221539
DOI	10.1152/ajpheart.00002.2009
Journal	AJP: Heart and Circulatory Physiology
Issue Number	6
Volume Number	296
Language	English
Publisher	American Physiological Society
Publisher Date	2009-06-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Physiology Discipline Cardiology Aldosterone Toxicity Apoptosis Drug Effects Fenofibrate Pharmacology Hypolipidemic Agents Map Kinase Signaling System Myocytes, Cardiac Animals Physiology Cell Survival Cells, Cultured Drug Interactions Jnk Mitogen-activated Protein Kinases Metabolism Mice Mice, Inbred Strains Mineralocorticoid Receptor Antagonists Mitochondria Mitogen-activated Protein Kinase 1 Mitogen-activated Protein Kinase 3 Cytology Ppar Alpha Agonists Proto-oncogene Proteins C-bcl-2 Rats, Sprague-dawley Spironolactone Analogs & Derivatives Bcl-2-associated X Protein P38 Mitogen-activated Protein Kinases Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Cardiology and Cardiovascular Medicine

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