VENTRICULAR EXPRESSION OF A MLC-2V-RAS FUSION GENE INDUCES CARDIAC-HYPERTROPHY AND SELECTIVE DIASTOLIC DYSFUNCTION IN TRANSGENIC MICE

p21(ras) 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 in duce in vivo hypertrophy, transgenic mice were created that express on cogenic ras in the cardiac ventricular chamber. Mice homozygous for th e transgene displayed morphological, physiological, and genetic marker s of marked cardiac muscle hypertrophy. Miniaturized catheterization t echnology documented a selective prolongation of cardiac relaxation, s imilar to that seen in early human hypertrophic heart disease, An incr ease in left atrial mass, in the absence of transgene expression in th at chamber, further supported physiologically abnormal left ventricula r diastolic function. Histological analysis revealed myofibrillar disa rray, indistinguishable from that in hypertrophic cardiomyopathy in ma n, These studies establish a ras-dependent pathway for hypertrophic he art disease and document the feasibility of mapping in vivo signaling pathways for cardiac hypertrophy and dysfunction by applying in vivo m icro-physiological assays to genetically manipulated mice, ras-depende nt pathways may also be a rational target for developing new approache s to inhibit the genesis of hypertrophy in certain pathological settin gs.