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Vol. 301, Issue 2, 459-466, May 2002
Department of Hypertension and Cardiorenal Medicine, Dokkyo
University School of Medicine, Mibu, Tochigi, Japan
Angiotensin II (Ang II) is a potent stimulator of plasminogen activator
inhibitor-1 (PAI-1) expression, which is an important regulator
of pathogenesis of atherosclerosis. Rho-kinase, a downstream target
protein of small GTP-binding protein Rho, plays a key role for various
cellular functions. We evaluated the cardioprotective effects of a
specific Rho-kinase inhibitor,
(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632), and an Ang II type 1 receptor antagonist,
candesartan, on PAI-1 gene expression and cardiovascular remodeling in
Ang II-induced hypertensive rats. Rats given Ang II alone (200 ng · kg
1 · min1) were compared with
rats also receiving Ang II plus Y-27632 or Ang II plus candesartan. Ang
II-induced PAI-1 mRNA up-regulation in the left ventricle was inhibited
by Y-27632 and candesartan. In addition, increased RhoA protein,
Rho-kinase, and c-fos gene expression, and myosin light
chain phosphorylation were suppressed by Y-27632 and candesartan. In
contrast, Y-27632 had no effect on Ang II-stimulated phospho-p42/p44
extracellular signal-regulated kinases (ERK) and phospho-p70S6 kinase
activities, which are reported to be involved in Ang II-induced protein
synthesis. Moreover, activated Ang II-induced phosphorylation of ERK
and p70S6 kinase were blocked by candesartan. Y-27632 or candesartan
administration resulted in significant improvements in the
wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis.
These results suggested that differential activation of Rho-kinase and
ERK pathways may play a critical role in Ang II-induce PAI-1 gene
expression, and up-regulation of Rho-kinase plays a key role in the
pathogenesis of Ang II-induced hypertensive rats. Thus, inhibition of
the Rho-kinase pathway may be at least a useful therapeutic strategy
for treating cardiovascular remodeling.
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