Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice.
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.
Duke Scholars
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Related Subject Headings
- Ventricular Dysfunction, Left
- Signal Transduction
- Recombinant Fusion Proteins
- Rats
- Proto-Oncogene Proteins p21(ras)
- Polymerase Chain Reaction
- Myocardium
- Myocardial Contraction
- Molecular Sequence Data
- Mice, Transgenic
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Ventricular Dysfunction, Left
- Signal Transduction
- Recombinant Fusion Proteins
- Rats
- Proto-Oncogene Proteins p21(ras)
- Polymerase Chain Reaction
- Myocardium
- Myocardial Contraction
- Molecular Sequence Data
- Mice, Transgenic