Absence of Rgs5 prolongs cardiac repolarization and predisposes to ventricular tachyarrhythmia in mice.
The aim of this study was to elucidate the effects of regulator of G-protein signaling 5 (Rgs5), a negative regulator of G-protein-mediated signaling, on cardiac repolarization and arrhythmia in mice. Wild-type and Rgs5(-/-) mice were subjected to in vivo, in vitro, and cellular electrophysiological experiments. Rgs5(-/-) mouse hearts showed significantly prolonged cardiac repolarization, including prolonged QT interval and action potential duration (APD). Consistent with these findings, measurement of K(+) currents in ventricular myocytes of Rgs5(-/-) mice revealed significant reduction of the outward voltage-dependent K(+) currents, including I(peak), I(to,)I(Kur), and I(ss), compared to that in wild-type mice. Transcript and protein expression levels of Kv4.2, Kv4.3, Kv1.5, and Kv2.1 were downregulated in Rgs5(-/-) mouse ventricles compared with those in wild-type mice (P<0.05). In addition, electrically induced ventricular tachyarrhythmias were facilitated by Rgs5(-/-) in isolated hearts. Importantly, the increased incidence and duration of electrically induced ventricular tachyarrhythmias were associated with enhanced dispersion of APD and spatial heterogeneity of I(peak), I(to) and I(Kur) between the epicardium and endocardium in the Rgs5(-/-) heart. This study showed the relationship between the absence of Rgs5 and cardiac electrophysiological abnormality. The results strongly indicate that Rgs5(-/-) induced prolonged repolarization and ventricular tachyarrhythmia, which were closely related to the remodeling of voltage-dependent K(+) currents.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Mu
M
Qin
He
H
Huang
Teng
T
Wang
He
H
Hu
Yu
Y
Liu
Hong
H
Cao
Hongliang
H
Li
Congxin
C
Huang
D000200:Action Potentials; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004562:Electrocardiography; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000503:physiopathology
D015221:Potassium Channels; D020710:RGS Proteins; D044140:Receptor, Angiotensin, Type 1; C105346:Rgs5 protein, mouse; D000804:Angiotensin II; D011188:Potassium