Involvement of Rho-Kinase Pathway for Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Gene Expression and Cardiovascular Remodeling in Hypertensive Rats

• Published in: The Journal of pharmacology and experimental therapeutics 2002-05, Vol.301 (2), p.459-466
• Main Authors: Kobayashi, Naohiko, Nakano, Shigefumi, Mita, Shin-ichiro, Kobayashi, Tsutomu, Honda, Takeaki, Tsubokou, Yusuke, Matsuoka, Hiroaki
• Format: Article
• Language: English
• Subjects: Amides - pharmacology; Angiotensin II - metabolism; Animals; Benzimidazoles - pharmacology; Body Weight - drug effects; Hemodynamics - drug effects; Hypertension - chemically induced; Hypertension - metabolism; Hypertension - physiopathology; Intracellular Signaling Peptides and Proteins; Male; Mitogen-Activated Protein Kinases - metabolism; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type III; Organ Size - drug effects; Plasminogen Activator Inhibitor 1 - biosynthesis; Plasminogen Activator Inhibitor 1 - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-fos - biosynthesis; Pyridines - pharmacology; Rats; Rats, Inbred WKY; rho-Associated Kinases; rhoA GTP-Binding Protein - biosynthesis; Ribosomal Protein S6 Kinases - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects; Tetrazoles - pharmacology; Ventricular Remodeling
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.301.2.459

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 · min −1 ) 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.