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FASEB J ; 20(7): 916-25, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16675849


Ventricular myocyte hypertrophy is an important compensatory growth response to pressure overload. However, pathophysiological cardiac hypertrophy is accompanied by reactive fibrosis and remodeling. The Rho kinase family, consisting of ROCK1 and ROCK2, has been implicated in cardiac hypertrophy and ventricular remodeling. However, these previous studies relied heavily on pharmacological inhibitors,and not on gene deletion. Here we used ROCK1knockout (ROCK1-/-) mice to investigate role of ROCK1 in the development of ventricular remodeling induced by transverse aortic banding. We observed that ROCK1 deletion did not impair compensatory hypertrophic response induced by pressure overload. However, ROCK1-/- mice exhibited reduced perivascular and interstitial fibrosis, which was observed at 3 wk but not at 1 wk after the banding. The reduced fibrosis in the myocardium of ROCK1-/- mice was closely associated with reduced expression of a variety of extracellular matrix (ECM) proteins and fibrogenic cytokines such as TGFbeta2 and connective tissue growth factor. This inhibitory effect of ROCK1 deletion on pathophysiological induction of fibrogenic cytokines was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of Gq. Thus, these results indicate that ROCK1 contributes to the development of cardiac fibrosis and induction of fibrogenic cytokines in cardiomyocytes in response to pathological stimuli.

Cardiomegalia/metabolismo , Fibrose/metabolismo , Fibrose/prevenção & controle , Coração/fisiopatologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Fibrose/patologia , Regulação Enzimológica da Expressão Gênica , Genótipo , Coração/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Knockout , Fenótipo , Pressão , Proteínas Serina-Treonina Quinases/genética , Remodelação Ventricular/fisiologia , Quinases Associadas a rho
J Mol Cell Cardiol ; 38(4): 685-91, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15808845


Conditional transgene expression in the heart is a useful approach to explore the physiological basis of the cardiac phenotype. The present study describes the development of a binary transgenic system in which transgene expression in the mouse heart can be turned on/off by administration/withdrawal of an exogenous compound. We generated a transgenic line (alphaMHC-Glp 65) harboring a mifepristone (RU486)-controlled chimeric transcription factor (Glp 65) under the regulatory control of the cardiac-specific alpha-myosin heavy chain (alphaMHC) promoter. In the presence of RU486, Glp 65 expressed in the heart is able to bind to a target gene promoter containing four copies of the 17-mer GAL4 binding site, resulting in ligand-inducible transactivation of the target gene. We tested this system by crossing the transgenic mice, alphaMHC-Glp 65, with a transgenic line harboring human growth hormone (hGH) target gene. We observed that expression of hGH could be induced in adults as well as in the embryonic hearts of bigenic mice by RU486. The basal hGH expression was very low and the inducible level in the heart was estimated over 800-fold higher versus the basal level after 4 days of administration of RU486 at 500 microg/kg body weight per day at 2-5 months of age. The level of the transgene returned to the basal level within 7 days after withdrawal of RU486. This system can be used to control cardiac-specific expression of transgene in a time- and dose-dependent manner.

Regulação da Expressão Gênica , Camundongos Transgênicos/genética , Miosinas Ventriculares/genética , Animais , Marcação de Genes , Hormônio do Crescimento/análise , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Ventrículos do Coração/química , Ventrículos do Coração/citologia , Humanos , Ligantes , Camundongos , Camundongos Transgênicos/metabolismo , Mifepristona/farmacologia , Cadeias Pesadas de Miosina/genética , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transativadores/genética , Transativadores/metabolismo , Transgenes , Regulação para Cima
FASEB J ; 18(7): 857-9, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15033930


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.

Nó Atrioventricular/fisiopatologia , Cardiomiopatia Hipertrófica/enzimologia , Inibidores de Dissociação do Nucleotídeo Guanina/fisiologia , Bloqueio Cardíaco/etiologia , Miócitos Cardíacos/metabolismo , Transdução de Sinais/fisiologia , Função Ventricular Esquerda , Adaptação Fisiológica , Animais , Cardiomiopatia Hipertrófica/fisiopatologia , Bovinos , Conexina 43/biossíntese , Conexina 43/genética , Conexinas/biossíntese , Conexinas/genética , Progressão da Doença , Regulação da Expressão Gênica , Inibidores de Dissociação do Nucleotídeo Guanina/genética , Átrios do Coração/anormalidades , Bloqueio Cardíaco/fisiopatologia , Heterozigoto , Camundongos , Camundongos Transgênicos , Cadeias Pesadas de Miosina/genética , Regiões Promotoras Genéticas , Transgenes , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Proteínas rho de Ligação ao GTP/fisiologia , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho , Inibidores da Dissociação do Nucleotídeo Guanina rho-Específico