Involvement of Rho-kinase pathway for angiotensin II-induced plasminogen activator inhibitor-1 gene expression and cardiovascular remodeling in hypertensive rats.
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.
Kobayashi
Naohiko
N
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. a-fukuda@dokkyomed.ac.jp
Nakano
Shigefumi
S
Mita
Shin-ichiro
S
Kobayashi
Tsutomu
T
Honda
Takeaki
T
Tsubokou
Yusuke
Y
Matsuoka
Hiroaki
H
D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001835:Body Weight / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D020257:Ventricular Remodeling; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis
D000577:Amides; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D047908:Intracellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D012333:RNA, Messenger; D013777:Tetrazoles; D000804:Angiotensin II; C108830:Y 27632; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; C081643:candesartan