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.
Hunter
J J
JJ
Department of Medicine, University of California-San Diego, School of Medicine, La Jolla, California 92093, USA.
Tanaka
N
N
Rockman
H A
HA
Ross
J
J
Chien
K R
KR
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured; D017931:DNA Primers; D003971:Diastole; D011905:Genes, ras; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006352:Heart Ventricles; D006720:Homozygote; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology*
D017931:DNA Primers; D011993:Recombinant Fusion Proteins; D008156:Luciferases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)