title: Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved.
abstract: 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 GDIalpha, an endogenous specific GDP dissociation inhibitor for Rho family proteins, using the alpha-myosin heavy-chain promoter. Increased expression of Rho GDIalpha 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.
authors.affiliation: Cardiovascular Sciences Section, Department of Medicine, Baylor College of Medicine and The Methodist Hospital, Houston, Texas 77030, USA. lwei@bcm.tmc.edu
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Dirar S
authors.initials: DS
authors.lastname: Khoury
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bo
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Atsuko
authors.initials: A
authors.lastname: Yatani
authors.forename: M Craig
authors.initials: MC
authors.lastname: Delaughter
authors.forename: Raisa
authors.initials: R
authors.lastname: Klevitsky
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Hewett
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Michael
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001283:Atrioventricular Node / Q000503:physiopathology*; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology* / Q000503:physiopathology; D002417:Cattle; D018031:Connexin 43 / Q000096:biosynthesis / Q000235:genetics; D017630:Connexins / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D005786:Gene Expression Regulation; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000502:physiology*; D006325:Heart Atria / Q000002:abnormalities; D006327:Heart Block / Q000209:etiology* / Q000503:physiopathology; D006579:Heterozygote; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology*; D019076:Transgenes; D016277:Ventricular Function, Left; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D000097003:Gap Junction alpha-5 Protein
chemical_list: D018031:Connexin 43; D017630:Connexins; D020730:Guanine Nucleotide Dissociation Inhibitors; D018995:Myosin Heavy Chains; D020741:rho GTP-Binding Proteins; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D000097003:Gap Junction alpha-5 Protein; C569639:Arhgdia protein, mouse