Ventricular Expression of a MLC-2v-ras Fusion Gene Induces Cardiac Hypertrophy and Selective Diastolic Dysfunction in Transgenic Mice

doi:10.1074/jbc.270.39.23173

Ventricular Expression of a MLC-2v-ras Fusion Gene Induces Cardiac Hypertrophy and Selective Diastolic Dysfunction in Transgenic Mice (*)

From the (1) Department of Medicine,
(2) Center for Molecular Genetics, and the
(3) American Heart Association-Bugher Foundation Center for Molecular Biology, University of California, San Diego, School of Medicine, La Jolla, California 92093

** To whom correspondence should be addressed:
Dept. of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0613.
Tel.: 619-534-6835; Fax: 619-534-8081.

Abstract

p21 has been implicated in the hypertrophic response of cultured cardiac myocytes to defined growth stimuli. To determine if activation of ras-dependent intracellular signaling pathways is sufficient to induce in vivo hypertrophy, transgenic mice were created that express oncogenic ras in the cardiac ventricular chamber. Mice homozygous for the transgene displayed morphological, physiological, and genetic markers of marked cardiac muscle hypertrophy. Miniaturized catheterization technology documented a selective prolongation of cardiac relaxation, similar to that seen in early human hypertrophic heart disease. An increase in left atrial mass, in the absence of transgene expression in that chamber, further supported physiologically abnormal left ventricular diastolic function. Histological analysis revealed myofibrillar disarray, indistinguishable from that in hypertrophic cardiomyopathy in man. These studies establish a ras-dependent pathway for hypertrophic heart disease and document the feasibility of mapping in vivo signaling pathways for cardiac hypertrophy and dysfunction by applying in vivo microphysiological assays to genetically manipulated mice. ras-dependent pathways may also be a rational target for developing new approaches to inhibit the genesis of hypertrophy in certain pathological settings.

Footnotes

↵^§ Supported by an American Heart Association-Bugher Foundation fellowship and CIA Grant HL03211 from NHLBI, National Institutes of Health.
↵^¶ Supported by a NHLBI Clinical Investigator Award.
↵* This work was supported by National Institutes of Health Grants HL36139, HL40569, and HL46345 and American Heart Association Grant 91-022170 (all to K. R. C.) and by National Institutes of Health Grant HL46345 and a chair from the San Diego Affiliate of the American Heart Association (both to J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹K. Wollert and K. R. Chien, submitted for publication.
↵² The abbreviations used are:

bp

base pair(s)

PCR

polymerase chain reaction

ANF

atrial natriuretic factor

RT

reverse transcriptase

LV

left ventricle

RV

right ventricle

HCM

hypertrophic cardiomyopathy.
- Received February 27, 1995.
- Revision received July 25, 1995.