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(Circulation. 2007;116:596-605.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Gi1-Mediated Cardiac Electrophysiological Remodeling and Arrhythmia in Hypertrophic Cardiomyopathy

Hongmei Ruan, MD, PhD; Scherise Mitchell, PhD; Monika Vainoriene, MD; Qing Lou, BA; Lai-Hua Xie, PhD; Shuxun Ren, MD; Joshua I. Goldhaber, MD; Yibin Wang, PhD

From the Division of Molecular Medicine, Departments of Anesthesiology (H.R., S.M., M.V., Q.L., Y.W.), Physiology (L.-H.X., S.R., J.I.G, Y.W.), and Medicine (J.I.G., Y.W.), Cardiovascular Research Laboratory (J.I.G, Y.W.), and Molecular Biology Institute (Y.W.), David Geffen School of Medicine, University of California at Los Angeles, Los Angeles.

Correspondence to Yibin Wang, PhD, Department of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratory, Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095. E-mail yibinwang{at}mednet.ucla.edu

Received December 7, 2006; accepted May 29, 2007.

Background— Cardiac hypertrophy is a major risk factor for arrhythmias and sudden cardiac death. However, the underlying signaling mechanisms involved in the induction of arrhythmia and electrophysiological remodeling in cardiac hypertrophy are unclear.

Methods and Results— Using an inducible gene-switch approach, we achieved tissue-specific and temporally regulated induction of a well-established hypertrophic pathway, the Ras-Raf–mitogen-activated protein kinases pathway, in adult mouse heart. On Ras activation, the transgenic animal developed ventricular hypertrophy and arrhythmias. The development of ventricular arrhythmias was temporally correlated with electrophysiological remodeling in isolated ventricular myocytes, including action potential prolongation, increased sodium-calcium exchanger activity, reduced outward potassium currents, sarcoplasmic reticulum Ca²⁺ defects, and loss of protein kinase A–dependent phospholamban phosphorylation. From genome-wide expression profiling, we discovered a selective induction of G inhibiting subunit 1 (Gi1) expression in the Ras transgenic heart. Treatment of transgenic animals with the Gi/o inhibitor pertussis toxin normalized the phospholamban phosphorylation by protein kinase A, reversed the action potential prolongation, and significantly reduced the frequency of cardiac arrhythmias in Ras transgenic animals.

Conclusions— These data suggest that selective induction of G inhibiting subunit 1 expression and activity is a novel downstream event in hypertrophic signaling that may be a critical factor leading to cellular electrophysiological remodeling and cardiac arrhythmias in hypertrophic cardiomyopathy.

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