title: Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure.
abstract: The Gq-RhoA-Rho kinase pathway, activated by neurohormonal factors such as angiotensin II (Ang II), has been proposed to be one of the important signaling pathways involved in the progression of left ventricular (LV) hypertrophy to heart failure. We tested the hypothesis that chronic inhibition of Rho kinase prevents this process. Heart failure was induced in Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from 8 until 17 weeks of age. Y-27632 (5 mg/kg per day), a selective Rho kinase inhibitor, was applied orally to DS rats starting at 10 weeks of age for 7 weeks (DS/Y+). DS rats without Y-27632 (DS/Y-) and Dahl salt-resistant (DR) rats fed the 8% NaCl diet were regarded as non-therapeutic and normotensive controls, respectively. At 17 weeks of age, there was no significant difference in the blood pressure of DS/Y- and DS/Y+ rats. DS/Y- rats exhibited: (1) increases in LV mass, cross-sectional area (CSA) of cardiomyocytes, and interstitial fibrosis; (2) contractile dysfunction, i.e. decreases in LV ejection fraction and % fractional shortening, and prolongation of time to peak tension as well as to 50% relaxation in the twitch contraction of isolated papillary muscle; and (3) increases in the protein expression of Galphaq and Rho kinase in the myocardial membrane fraction. In DS/Y+ rats, the degree of myocardial hypertrophy was significantly inhibited in association with improved contractile function, without a decrease in the degree of interstitial fibrosis. Our results suggest the possibility that the Gq-Rho kinase pathway plays an important role in the process of hypertension-induced LV hypertrophy leading to contractile dysfunction.
authors.affiliation: Department of Bioclimatology and Medicine, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, 874-0838, Beppu, Japan. satoshin@tsurumi.beppu.kyushu-u.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Satoh
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ueda
authors.forename: Masamichi
authors.initials: M
authors.lastname: Koyanagi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kadokami
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sugano
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Makino
mesh_terms: D000577:Amides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D009206:Myocardium / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014463:Ultrasonography; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins