Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats.
Chronic inhibition of endothelial NO synthesis by the administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 expression) as well as subsequent arteriosclerosis. The small GTPase Rho controls cell adhesion, motility, and proliferation and is activated by several growth factors such as angiotensin II. We investigated the effect of a specific inhibitor of Rho-kinase, Y-27632, in rats treated with L-NAME to determine the role of the Rho/Rho-kinase pathway in the development of arteriosclerosis. We found here increased activity of Rho/Rho-kinase after L-NAME administration and its prevention by angiotensin II type 1 receptor blockade. Hydralazine or lecithinized superoxide dismutase (l-SOD) did not affect Rho/Rho-kinase activity. Co-treatment with Y-27632 did not affect the L-NAME-induced increase in cardiovascular tissue ACE activity or L-NAME-induced decrease in plasma NO concentrations, but did prevent the L-NAME-induced early inflammation and late coronary arteriosclerosis. In addition, Y-27632 prevented the increased gene expression of monocyte chemoattractant protein-1 and transforming growth factor-beta1 as well as cardiac fibrosis and glomerulosclerosis. These findings suggest that increased activity of Rho/Rho-kinase pathway mediated via the angiotensin II type 1 receptor may thus be important in the pathogenesis of early vascular inflammation and late remodeling induced by chronic inhibition of NO synthesis. The beneficial effects of Rho-kinase inhibition are not mediated by restoration of NO production. The Rho-kinase pathway could be a new therapeutic target for treatment of vascular diseases.
Kataoka
Chu
C
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Egashira
Kensuke
K
Inoue
Shujiro
S
Takemoto
Masao
M
Ni
Weihua
W
Koyanagi
Masamichi
M
Kitamoto
Shiro
S
Usui
Makoto
M
Kaibuchi
Kozo
K
Shimokawa
Hiroaki
H
Takeshita
Akira
A
D000199:Actins / Q000032:analysis; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000235:genetics; D003331:Coronary Vessels / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006830:Hydralazine / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology* / Q000209:etiology; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D009130:Muscle, Smooth / Q000737:chemistry; D009218:Myosins / Q000378:metabolism; D016328:NF-kappa B / Q000032:analysis; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D013482:Superoxide Dismutase / Q000494:pharmacology; D013777:Tetrazoles; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D054460:rho-Associated Kinases
D000199:Actins; D000577:Amides; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D011725:Pyridines; D012333:RNA, Messenger; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C108830:Y 27632; D006830:Hydralazine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D007703:Peptidyl-Dipeptidase A; D009218:Myosins; C077793:candesartan cilexetil; D019331:NG-Nitroarginine Methyl Ester