Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure

Shinji Satoh, Yasuko Ueda, Masamichi Koyanagi, Toshiaki Kadokami, Masahiro Sugano, Yasuji Yoshikawa, Naoki Makino

Research output: Contribution to journalArticle

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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 Gαq 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.

Original languageEnglish
Pages (from-to)59-70
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume35
Issue number1
DOIs
Publication statusPublished - Jan 1 2003

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Inbred Dahl Rats
rho-Associated Kinases
Left Ventricular Hypertrophy
Heart Failure
Hypertension
Fibrosis
Salts
Gq-G11 GTP-Binding Protein alpha Subunits
Diet
Papillary Muscles
Cardiac Myocytes
Angiotensin II
Stroke Volume
Hypertrophy
Blood Pressure
Membranes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure. / Satoh, Shinji; Ueda, Yasuko; Koyanagi, Masamichi; Kadokami, Toshiaki; Sugano, Masahiro; Yoshikawa, Yasuji; Makino, Naoki.

In: Journal of Molecular and Cellular Cardiology, Vol. 35, No. 1, 01.01.2003, p. 59-70.

Research output: Contribution to journalArticle

Satoh, Shinji ; Ueda, Yasuko ; Koyanagi, Masamichi ; Kadokami, Toshiaki ; Sugano, Masahiro ; Yoshikawa, Yasuji ; Makino, Naoki. / Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure. In: Journal of Molecular and Cellular Cardiology. 2003 ; Vol. 35, No. 1. pp. 59-70.
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