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(Received for publication, February 27,
1995; and in revised form, July 25, 1995) p21
Volume 270,
Number 39,
Issue of September 29, pp. 23173-23178, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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.
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P. D. Ho, D. K. Zechner, H. He, W. H. Dillmann, C. C. Glembotski, and P. M. McDonough The Raf-MEK-ERK Cascade Represents a Common Pathway for Alteration of Intracellular Calcium by Ras and Protein Kinase C in Cardiac Myocytes J. Biol. Chem., August 21, 1998; 273(34): 21730 - 21735. [Abstract] [Full Text] [PDF]
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L. Cao, L. Zhang, P. Ruiz-Lozano, Q. Yang, K. R. Chien, R. M. Graham, and M. Zhou A Novel Putative Protein-tyrosine Phosphatase Contains a BRO1-like Domain and Suppresses Ha-ras-mediated Transformation J. Biol. Chem., August 14, 1998; 273(33): 21077 - 21083. [Abstract] [Full Text] [PDF]
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