RGD Reference Report - Antiapoptotic effect of endothelin-1 in rat cardiomyocytes in vitro. - Rat Genome Database

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Antiapoptotic effect of endothelin-1 in rat cardiomyocytes in vitro.

Authors: Ogata, Y  Takahashi, M  Ueno, S  Takeuchi, K  Okada, T  Mano, H  Ookawara, S  Ozawa, K  Berk, BC  Ikeda, U  Shimada, K  Kobayashi, E 
Citation: Ogata Y, etal., Hypertension. 2003 May;41(5):1156-63. Epub 2003 Mar 31.
RGD ID: 1642633
Pubmed: PMID:12668584   (View Abstract at PubMed)
DOI: DOI:10.1161/01.HYP.0000064342.30653.24   (Journal Full-text)

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 ETA 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-xL, an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-xL, 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-xL expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ETA receptor and the subsequent c-Src/Bcl-xL-dependent pathway.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of muscle cell apoptotic process  IMP 1642633 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ptk2b  (protein tyrosine kinase 2 beta)


Additional Information