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(Hypertension. 2003;41:1156.)
© 2003 American Heart Association, Inc.

Scientific Contributions

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; 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.

Correspondence to Masafumi Takahashi, MD, PhD, Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Minamikawachi-machi, Tochigi 329-0498, Japan. E-mail masafumi{at}jichi.ac.jp

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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