title: Crucial role of rho-kinase in pressure overload-induced right ventricular hypertrophy and dysfunction in mice.
abstract: OBJECTIVE
  Right ventricular (RV) failure is the leading cause of death in various cardiopulmonary diseases, including pulmonary hypertension. It is generally considered that the RV is vulnerable to pressure overload as compared with the left ventricle (LV). However, as compared with LV failure, the molecular mechanisms of RV failure are poorly understood, and hence therapeutic targets of the disorder remain to be elucidated. Thus, we aimed to identify molecular therapeutic targets for RV failure in a mouse model of pressure overload.
  
  
  RESULTS
  To induce pressure overload to respective ventricles, we performed pulmonary artery constriction or transverse aortic constriction in mice. We first performed microarray analysis and found that the molecules related to RhoA/Rho-kinase and integrin pathways were significantly upregulated in the RV with pulmonary artery constriction compared with the LV with transverse aortic constriction. Then, we examined the responses of both ventricles to chronic pressure overload in vivo. We demonstrated that compared with transverse aortic constriction, pulmonary artery constriction caused greater extents of mortality, Rho-kinase expression (especially ROCK2 isoform), and oxidative stress in pressure-overloaded RV, reflecting the weakness of the RV in response to pressure overload. Furthermore, mice with myocardial-specific overexpression of dominant-negative Rho-kinase showed resistance to pressure overload-induced hypertrophy and dysfunction associated with reduced oxidative stress. Finally, dominant-negative Rho-kinase mice showed a significantly improved long-term survival in both pulmonary artery constriction and transverse aortic constriction as compared with littermate controls.
  
  
  CONCLUSIONS
  These results indicate that the Rho-kinase pathway plays a crucial role in RV hypertrophy and dysfunction, suggesting that the pathway is a novel therapeutic target of RV failure in humans.
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Shohei
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kikuchi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Kota
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Junichi
authors.initials: J
authors.lastname: Omura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Toru
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Kenta
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi).
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (S.I., K.S., N.K., S.M., K.S., J.O., T.S., Y.F., Y.S., H.S.); and Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan (Ke. Kobayashi, Ka. Kobayashi). shimo@cardio.med.tohoku.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005355:Fibrosis; D050991:GATA4 Transcription Factor / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000150:complications; D017380:Hypertrophy, Right Ventricular / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D015398:Signal Transduction / Q000502:physiology; D018497:Ventricular Dysfunction, Right / Q000209:etiology*; D054460:rho-Associated Kinases / Q000502:physiology*
chemical_list: D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: heart failure, right-sided; hypertrophy, right ventricular; oxidative stress; rho-associated kinases