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Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in
J J Hunter1, N Tanaka, H A Rockman
1Department of Medicine, University of California-San Diego, School of Medicine, La Jolla, California 92093, USA.
Abstract:
p21ras 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.
Insights
Activation of ras signaling in mice causes cardiac hypertrophy, mimicking human heart disease. This study identifies a ras-dependent pathway for hypertrophy, suggesting potential therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetics
Background:
- p21ras is involved in cardiac myocyte hypertrophy in cell cultures.
- The role of ras-dependent signaling in inducing in vivo cardiac hypertrophy is not fully understood.
Purpose of the Study:
- To investigate if activating ras-dependent intracellular signaling pathways is sufficient to cause cardiac hypertrophy in living organisms.
- To establish a ras-dependent pathway for hypertrophic heart disease.
Main Methods:
- Created transgenic mice expressing oncogenic ras in the cardiac ventricular chamber.
- Utilized miniaturized catheterization technology for physiological assessment.
- Performed histological analysis to examine cardiac muscle structure.
Main Results:
- Transgenic mice exhibited significant cardiac muscle hypertrophy with morphological, physiological, and genetic markers.
- Observed prolonged cardiac relaxation and increased left atrial mass, indicative of diastolic dysfunction.
- Histology revealed myofibrillar disarray similar to human hypertrophic cardiomyopathy.
Conclusions:
- Ras-dependent pathways are sufficient to induce cardiac hypertrophy in vivo.
- Demonstrated the feasibility of mapping in vivo signaling pathways for cardiac hypertrophy using genetically modified mice.
- Ras-dependent pathways represent a potential target for inhibiting hypertrophy in pathological conditions.