Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats

Chu Kataoka, Kensuke Egashira, Shujiro Inoue, Masao Takemoto, Weihua Ni, Masamichi Koyanagi, Shiro Kitamoto, Makoto Usui, Kozo Kaibuchi, Hiroaki Shimokawa, Akira Takeshita

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Abstract

Chronic inhibition of endothelial NO synthesis by the administration of NG-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 (1-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-β1 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.

Original languageEnglish
Pages (from-to)245-250
Number of pages6
JournalHypertension
Volume39
Issue number2 I
DOIs
Publication statusPublished - Mar 4 2002

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rho-Associated Kinases
NG-Nitroarginine Methyl Ester
Nitric Oxide
Inflammation
Angiotensin Type 1 Receptor
Arteriosclerosis
Chemokine CCL2
Blood Vessels
Hydralazine
Monomeric GTP-Binding Proteins
Transforming Growth Factors
Vascular Diseases
Cell Adhesion
Angiotensin II
Cell Movement
Coronary Artery Disease
Monocytes
Intercellular Signaling Peptides and Proteins
Coronary Vessels
Fibrosis

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. / Kataoka, Chu; Egashira, Kensuke; Inoue, Shujiro; Takemoto, Masao; Ni, Weihua; Koyanagi, Masamichi; Kitamoto, Shiro; Usui, Makoto; Kaibuchi, Kozo; Shimokawa, Hiroaki; Takeshita, Akira.

In: Hypertension, Vol. 39, No. 2 I, 04.03.2002, p. 245-250.

Research output: Contribution to journalArticle

Kataoka, C, Egashira, K, Inoue, S, Takemoto, M, Ni, W, Koyanagi, M, Kitamoto, S, Usui, M, Kaibuchi, K, Shimokawa, H & Takeshita, A 2002, 'Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats', Hypertension, vol. 39, no. 2 I, pp. 245-250. https://doi.org/10.1161/hy0202.103271
Kataoka, Chu ; Egashira, Kensuke ; Inoue, Shujiro ; Takemoto, Masao ; Ni, Weihua ; Koyanagi, Masamichi ; Kitamoto, Shiro ; Usui, Makoto ; Kaibuchi, Kozo ; Shimokawa, Hiroaki ; Takeshita, Akira. / Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. In: Hypertension. 2002 ; Vol. 39, No. 2 I. pp. 245-250.
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AU - Takemoto, Masao

AU - Ni, Weihua

AU - Koyanagi, Masamichi

AU - Kitamoto, Shiro

AU - Usui, Makoto

AU - Kaibuchi, Kozo

AU - Shimokawa, Hiroaki

AU - Takeshita, Akira

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N2 - Chronic inhibition of endothelial NO synthesis by the administration of NG-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 (1-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-β1 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.

AB - Chronic inhibition of endothelial NO synthesis by the administration of NG-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 (1-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-β1 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.

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