Ventricular expression of a mlc-2v-ras fusion gene induces cardiac hypertrophy selective diastolic dysfunction in transgenic mice

Abstract

p21ras has been implicated in the hypertrophie response of cultured cardiac myocytes to defined growth stimuli. To determine if activation of ros-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 hypertrophie 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 hypertrophie cardiomyopathy in man. These studies establish a ras-dependent pathway for hypertrophie 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.