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Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved
Author(s) -
Wei Lei,
Taffet George E.,
Khoury Dirar S.,
Bo Jacqueline,
Li Yi,
Yatani Atsuko,
Delaughter M. Craig,
Klevitsky Raisa,
Hewett Timothy E.,
Robbins Jeffrey,
Michael Lloyd H.,
Schneider Michael D.,
Entman Mark L.,
Schwartz Robert J.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0664fje
Subject(s) - medicine , cardiology , muscle hypertrophy , endocrinology , cardiac function curve , electrical conduction system of the heart , intracardiac injection , rhoa , heart failure , biology , signal transduction , electrocardiography , microbiology and biotechnology
Recent studies suggest that RhoA and Rac1 mediate hypertrophic signals in cardiac myocyte hypertrophy. However, effects on cardiac function caused by inhibition of their activity in the heart have yet to be evaluated. Cardiac‐specific inhibition of Rho family protein activities was achieved by expressing Rho GDIα, an endogenous specific GDP dissociation inhibitor for Rho family proteins, using the α‐myosin heavy‐chain promoter. Increased expression of Rho GDIα led to atrial arrhythmias and mild ventricular hypertrophy in adult mice (4–7 months). However, left ventricular systolic and diastolic function was largely preserved before and after the development of cardiac hypertrophy, indicating that Rho GTPases are not required to maintain ventricular contractile function under basal physiological condition. Electrocardiography and intracardiac electrophysiological studies revealed first‐degree atrioventricular (AV) block in the transgenic heart at 1 week of age, which further progressed into second‐degree AV block at 4 weeks of age before the development of cardiac hypertrophy. Expression of connexin 40 dramatically decreased from 1 week to 4 weeks of age in the transgenic heart, which may contribute in part to the conduction defects in the transgenic mice. This study provides novel evidence for an important role of Rho GTPases in regulating AV conduction.