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Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure
Valerie P. Sah, … , Kenneth R. Chien, Joan Heller Brown
Valerie P. Sah, … , Kenneth R. Chien, Joan Heller Brown
Published June 15, 1999
Citation Information: J Clin Invest. 1999;103(12):1627-1634. https://doi.org/10.1172/JCI6842.
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Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure

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Abstract

RhoA is a low-molecular-weight GTPase that has been implicated in the regulation of hypertrophic cardiac muscle cell growth. To study the role of RhoA in control of cardiac function in vivo, transgenic mice expressing wild-type and constitutively activated forms of RhoA under the control of the cardiac-specific α-myosin heavy chain promoter were generated. Transgene-positive mice expressing high levels of either wild-type or activated RhoA showed pronounced atrial enlargement and manifested a lethal phenotype, often preceded by generalized edema, with most animals dying over the course of a few weeks. Echocardiographic analysis of visibly healthy wild-type RhoA transgenic mice revealed no significant change in left ventricular function. As their condition deteriorated, significant dilation of the left ventricular chamber and associated decreases in left ventricular contractility were detected. Heart rate was grossly depressed in both wild-type and activated RhoA-expressing mice, even prior to the onset of ventricular failure. Electrocardiography showed evidence of atrial fibrillation and atrioventricular block. Interestingly, muscarinic receptor blockade with atropine did not elicit a positive chronotropic response in the transgenic mice. We suggest that RhoA regulates cardiac sinus and atrioventricular nodal function and that its overexpression results in bradycardia and development of ventricular failure.

Authors

Valerie P. Sah, Susumu Minamisawa, Steven P. Tam, Thomas H. Wu, Gerald W. Dorn II, John Ross Jr., Kenneth R. Chien, Joan Heller Brown

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Survival analysis of RhoA transgenic mice. F1 heterozygotes were generat...
Survival analysis of RhoA transgenic mice. F1 heterozygotes were generated by backcrossing the V12 founder mouse with either Black Swiss or C57BL/6 mice. The open triangles represent percent survival of nontransgenic (NTG) F1 mice (n = 55); the filled squares represent survival of transgenic (TG) V12 × Black Swiss F1 mice (n = 15); the filled circles represent survival of transgenic V12 × C57BL/6 F1 mice (n = 8).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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