Involvement of Rho-kinase pathway for angiotensin II-induced plasminogen activator inhibitor-1 gene expression and cardiovascular remodeling in hypertensive rats.

Abstract

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.

• Authors: Naohiko Kobayashi, Shigefumi Nakano, Shin-ichiro Mita, Tsutomu Kobayashi, Takeaki Honda, Yusuke Tsubokou, Hiroaki Matsuoka
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 301 Issue 2 Pg. 459-66 (May 2002) ISSN: 0022-3565 [Print] United States
• PMID: 11961044 (Publication Type: Journal Article)

Chemical References

• Amides
• Benzimidazoles
• Biphenyl Compounds
• Intracellular Signaling Peptides and Proteins
• Plasminogen Activator Inhibitor 1
• Proto-Oncogene Proteins c-fos
• Pyridines
• RNA, Messenger
• Tetrazoles
• Angiotensin II
• Y 27632
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type III
• Nos3 protein, rat
• Protein Serine-Threonine Kinases
• Ribosomal Protein S6 Kinases
• rho-Associated Kinases
• Mitogen-Activated Protein Kinases
• rhoA GTP-Binding Protein
• candesartan

Topics

• Amides (pharmacology)
• Angiotensin II (metabolism)
• Animals
• Benzimidazoles (pharmacology)
• Biphenyl Compounds
• Body Weight (drug effects)
• Hemodynamics (drug effects)
• Hypertension (chemically induced, metabolism, physiopathology)
• Intracellular Signaling Peptides and Proteins
• Male
• Mitogen-Activated Protein Kinases (metabolism)
• Nitric Oxide Synthase (genetics, metabolism)
• Nitric Oxide Synthase Type III
• Organ Size (drug effects)
• Plasminogen Activator Inhibitor 1 (biosynthesis, genetics)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-fos (biosynthesis)
• Pyridines (pharmacology)
• RNA, Messenger (biosynthesis, drug effects)
• Rats
• Rats, Inbred WKY
• Ribosomal Protein S6 Kinases (metabolism)
• Tetrazoles (pharmacology)
• Ventricular Remodeling
• rho-Associated Kinases
• rhoA GTP-Binding Protein (biosynthesis)