Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / analysis
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Amides / pharmacology*
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Animals
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Benzimidazoles / pharmacology
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Biphenyl Compounds / pharmacology
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Blood Pressure / drug effects
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Cardiovascular Diseases / enzymology*
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Cardiovascular Diseases / etiology
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Cardiovascular Diseases / physiopathology
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Chemokine CCL2 / genetics
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Coronary Vessels / chemistry
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Coronary Vessels / drug effects
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Coronary Vessels / pathology
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Enzyme Inhibitors / pharmacology*
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Hydralazine / pharmacology
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Immunohistochemistry
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Inflammation / enzymology*
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Inflammation / etiology
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Intracellular Signaling Peptides and Proteins
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Kidney Glomerulus / drug effects
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Kidney Glomerulus / pathology
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Muscle, Smooth / chemistry
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Myosins / metabolism
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NF-kappa B / analysis
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NG-Nitroarginine Methyl Ester / pharmacology
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Nitric Oxide / antagonists & inhibitors*
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism
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Peptidyl-Dipeptidase A / metabolism
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Phosphorylation / drug effects
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Proliferating Cell Nuclear Antigen / analysis
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism*
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Pyridines / pharmacology*
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Inbred WKY
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Superoxide Dismutase / pharmacology
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Tetrazoles*
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Time Factors
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta1
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rho-Associated Kinases
Substances
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Actins
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Amides
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Benzimidazoles
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Biphenyl Compounds
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Chemokine CCL2
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Proliferating Cell Nuclear Antigen
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Pyridines
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RNA, Messenger
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Tetrazoles
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Tgfb1 protein, rat
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Y 27632
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Hydralazine
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Nitric Oxide
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Nitric Oxide Synthase
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Superoxide Dismutase
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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Peptidyl-Dipeptidase A
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Myosins
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candesartan cilexetil
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NG-Nitroarginine Methyl Ester