Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure

RhoA is a low-molecular-weight GTPase that has been implicated in the regul ation of hypertrophic cardiac muscle cell growth. To study the role of RhoA in control of cardiac function in vivo, transgenic mice expressing wild-ty pe and constitutively activated forms of RhoA under the control of the card iac-specific a-myosin heavy chain promoter were generated. Transgene-positi ve mice expressing high levels of either wild-type or activated RhoA showed pronounced atrial enlargement and manifested a lethal phenotype, often pre ceded by generalized edema, with most animals dying over the course of a fe w weeks. Echocardiographic analysis of visibly healthy wild-type RhoA trans genic 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 det ected. Heart rate was grossly depressed in both wild-type and activated Rho A-expressing mice, even prior to the onset of ventricular failure. Electroc ardiography showed evidence of atrial fibrillation and atrioventricular blo ck. Interestingly, muscarinic receptor blockade with atropine did not elici t a positive chronotropic response in the transgenic mice. We suggest that RhoA regulates cardiac sinus and atrioventricular nodal function and that i ts overexpression results in bradycardia and development of ventricular fai lure.