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 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 alpha-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.
Sah
V P
VP
Department of Pharmacology, University of California-San Diego, La Jolla, California 92093, USA.
Minamisawa
S
S
Tam
S P
SP
Wu
T H
TH
Dorn
G W
GW
Ross
J
J
Chien
K R
KR
Brown
J H
JH
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D001283:Atrioventricular Node / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000201:enzymology*; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D009929:Organ Size / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012849:Sinoatrial Node / Q000503:physiopathology*; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D009320:Atrial Natriuretic Factor; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D018995:Myosin Heavy Chains