Published Online
on March 31, 2003

A more recent version of this article appeared on May 1, 2003

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Submitted on July 10, 2002
Revised on September 23, 2002

Antiapoptotic Effect of Endothelin-1 in Rat Cardiomyocytes In Vitro

Yukiyo Ogata; Masafumi Takahashi^*; Shuichi Ueno; Koichi Takeuchi; Takashi Okada; Hiroyuki Mano; Shigeo Ookawara; Keiya Ozawa; Bradford C. Berk; Uichi Ikeda; Kazuyuki Shimada; and Eiji Kobayashi

From the Division of Cardiovascular Medicine (Y.O., M.T., S.U., U.I., K.S.), Department of Medicine; the Divisions of Organ Replacement Research (M.T., E.K.), Functional Genomes (S.U., H.M.), and Genetic Therapeutics (T.O., K.O.), Center for Molecular Medicine; and the Department of Anatomy (K.T., S.O.), Jichi Medical School, Tochigi, Japan, and the Center for Cardiovascular Research (B.C.B.), University of Rochester, Rochester, NY.

^* To whom correspondence should be addressed. E-mail: masafumi{at}jichi.ac.jp.

Abstract--Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders, including congestive heart failure (CHF) and ischemic heart disease (IHD). Because recent investigations indicate that endothelin-1 (ET-1) plays an important role in CHF and IHD, we investigated the effect of ET-1 on cardiomyocyte apoptosis. The presence of apoptosis in rat cardiomyocytes (H9c2 and neonatal) was evaluated by morphological criteria, electrophoresis of DNA fragments, 4',6'-diamidine-2'-phenylindole staining, and TUNEL analysis. ET-1, but not angiotensin II, prevented apoptosis induced by serum deprivation via ET_A receptors in a dose-dependent manner (1 to 100 nmol/L). ET-1 also prevented cytochrome c release from mitochondria to the cytosol. The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET-1 was mediated through a tyrosine kinase pathway (genistein and AG490) but not through protein kinase C (PKC; calphostin C), mitogen-activated protein kinases (PD98059 and SB203580), or PKA (KT5270) pathways. Adenovirus-mediated gene transfer of kinase-inactive (KI) c-Src reversed the antiapoptotic effect of ET-1. We further investigated whether Bcl-x_L, an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-x_L, and this upregulation was inhibited by genistein or AG490 but not by calphostin C. The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk2 (but not JAK1, Jak2, Syk, and Tec) are involved in ET-1-induced upregulation of Bcl-x_L expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ET_A receptor and the subsequent c-Src/Bcl-x_L-dependent pathway.

Key words: signal transduction • kinase • endothelin • apoptosis • myocardium

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