© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan
a-fukuda{at}dokkyomed.ac.jp
* Corresponding author. Tel.: +81-282-87-2149; fax: +81-282-86-1596
Objectives: Rho and Rho-kinase play a critical role in the regulation of cellular functions such as proliferation and migration. To elucidate the molecular mechanisms that regulate cardiac function and cardiovascular remodeling, we determined whether the signaling pathway through Rho is involved in Dahl salt-sensitive hypertensive rats with congestive heart failure (CHF) using a specific Rho-kinase inhibitor, Y-27632. Methods: Y-27632 was administered from the left ventricular hypertrophy stage (11 weeks) to the CHF stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure–volume relationship (contractility: Ees) was evaluated using a conductance catheter. Results: Downregulated Ees in the CHF stage was significantly ameliorated by Y-27632 treatment. Increased RhoA protein, Rho-kinase gene expression and myosin light chain phosphorylations in CHF rats were suppressed by Y-27632. Upregulated proto-oncogene c-fos gene expression in CHF rats was decreased by inhibiting Rho-kinase. In contrast, Y-27632 showed no effect on upregulated extracellular signal-regulated kinases (ERK) and p70S6 kinase phosphorylations, which were reported to be involved in protein synthesis. In the CHF stage, Y-27632 effectively inhibited vascular lesion formation such as medial thickness and perivascular fibrosis. Conclusions: These results suggest that differential activation of the Rho–Rho-kinase and the ERK–p70S6 kinase pathways may play a critical role in CHF, and the Rho–Rho-kinase pathway is involved in the pathogenesis of cardiac dysfunction and cardiovascular remodeling. Thus, inhibition of the Rho-kinase pathway may be at least a potential therapeutic strategy for CHF.
KEYWORDS Contractile function; G-proteins; Heart failure; Remodeling; Signal transduction
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