Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway

doi:10.1074/jbc.272.9.5783

Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway

DIVERGENCE FROM DOWNSTREAM CT-1 SIGNALS FOR MYOCARDIAL CELL HYPERTROPHY*

From the ^‡ Department of Medicine,
^§ Center for Molecular Genetics,
^∥ American Heart Association-Bugher Foundation Center for Molecular Biology, and
^¶¶ Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, California 92093

^a To whom correspondence should be addressed:
Dept. of Medicine, 0613-C, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613.
Tel.: 619-534-6835; Fax: 619-534-8081; E-mail: kchien{at}ucsd.edu

↵^¶ Former trainee under National Institutes of Health Training Grant T32HL07770. Present Address: Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, NJ 08543.

Abstract

Cardiac myocyte survival is of central importance in the maintenance of the function of heart, as well as in the development of a variety of cardiac diseases. To understand the molecular mechanisms that govern this function, we characterized apoptosis in cardiac muscle cells following serum deprivation. Cardiotrophin 1 (CT-1), a potent cardiac survival factor (Sheng, Z., Pennica, D., Wood, W. I., and Chien, K. R. (1996) Development (Camb.) 122, 419-428), is capable of inhibiting apoptosis in cardiac myocytes. To explore the potential downstream pathways that might be responsible for this effect, we documented that CT-1 activated both signal transducer and activator of transcription 3 (STAT3)- and mitogen-activated protein (MAP) kinase-dependent pathways. The transfection of a MAP kinase kinase 1 (MEK1) dominant negative mutant cDNA into myocardial cells blocked the antiapoptotic effects of CT-1, indicating a requirement of the MAP kinase pathway for the survival effect of CT-1. A MEK-specific inhibitor (PD098059) (Dudley, D. T., Pang, L., Decker, S.-J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci. USA 92, 7686-7689) is capable of blocking the activation of MAP kinase, as well as the survival effect of CT-1. In contrast, this inhibitor did not block the activation of STAT3, nor did it have any effect on the hypertrophic response elicited following stimulation of CT-1. Therefore, CT-1 promotes cardiac myocyte survival via the activation of an antiapoptotic signaling pathway that requires MAP kinases, whereas the hypertrophy induced by CT-1 may be mediated by alternative pathways, e.g. Janus kinase/STAT or MEK kinase/c-Jun NH₂-terminal protein kinase.

Footnotes

↵** Supported by California American Heart Association Grant-in-aid 96-303A.
↵^‡‡ Trainee under NIH Training Grant T32HL07770.
↵^§§ Supported by an American Heart Association postdoctoral fellowship award.
↵^∥∥ Supported by National Institutes of Health NHLBI Grants RO1 HL28143 and PO1 HL46345.
↵* This work was supported in part by National Institutes of Health NHLBI Grants 1 RO1 HL51549, PO1 HL46345, and HL53773 and American Heart Association Grant HL 91-022170 (to K. R. C.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

CT-1

cardiotrophin 1

MAP

mitogen-activated protein

MEK

MAP kinase kinase

STAT

signal transducer and activator of transcription

PBS

phosphate-buffered saline

IL-6

interleukin 6

LIF

leukemia inhibitory factor

JAK

Janus kinase

CNTF

ciliary neurotrophic factor

MLC-2v

ventricular myosin light chain 2

ANF

atrial natriuretic factor

ERK

extracellular regulated kinase

TUNEL

terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling.
↵² E. Jeon, Z. Sheng, and K. Knowlton et al., unpublished observations.
↵³ J. H. Brown, unpublished data.
↵⁴ K. R. Gottshall, J. J. Hunter, N. Tanaka, K. D. Becker, J. Ross, Jr., and K. R. Chien, manuscript in revision.
- Received October 7, 1996.
- Revision received December 23, 1996.