Mechanisms Underlying the Anti-inflammatory Effects of the Ca2+/Calmodulin Antagonist CV-159 in Cultured Vascular Smooth Muscle Cells
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- Usui Tatsuya
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
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- Yamawaki Hideyuki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
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- Kamibayashi Masato
- Kyoto Pharmaceutical University, Japan
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- Okada Muneyoshi
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
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- Hara Yukio
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
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抄録
CV-159 is a unique dihydropyridine Ca2+ antagonist with an anti-calmodulin (CaM) action. A pathogenic feature of atherosclerosis is vascular inflammatory change. In the present study, we examined whether CV-159 exerts protective effects on smooth muscle inflammatory responses. After pretreatment of rat mesenteric arterial smooth muscle cells (SMCs) with CV-159 (0.1 – 10 μM, 30 min), TNF-α (10 ng/ml) was applied for 20 min or 24 h. CV-159 inhibited TNF (24 h)–induced vascular cell adhesion molecule (VCAM)-1 as determined by Western blotting. CV-159 inhibited TNF (20 min)–induced phosphorylation of Akt (Ser473) and NF-κB p65 (Ser536). An Akt inhibitor, LY294002, and an NF-κB inhibitor, pyrrolidine dithiocarbamate, inhibited TNF-induced VCAM-1. An antioxidant drug, N-acetyl-L-cysteine (NAC) inhibited TNF-induced VCAM-1. NAC also inhibited TNF-induced phosphorylation of Akt and NF-κB. Furthermore, CV-159 inhibited TNF-induced reactive oxygen species (ROS) production as determined fluorometrically using dichlorodihydrofluorescein diacetate. A CaM inhibitor, W-7, and a calcium/CaM-dependent protein kinase type II inhibitor, KN93, inhibited TNF-induced VCAM-1. W-7 and KN93 inhibited TNF-induced phosphorylation of Akt but not NF-κB. The present results indicate that in vascular SMCs, CV-159 inhibits TNF-induced VCAM-1 through inhibition of NF-κB and Akt phosphorylation. CV-159 prevents NF-κB phosphorylation by inhibiting ROS, while it prevents Akt phosphorylation by inhibiting both ROS and CaM.
収録刊行物
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- Journal of Pharmacological Sciences
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Journal of Pharmacological Sciences 113 (3), 214-223, 2010
公益社団法人 日本薬理学会
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詳細情報 詳細情報について
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- CRID
- 1390001205179783808
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- NII論文ID
- 10029889201
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- NII書誌ID
- AA11806667
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- ISSN
- 13478648
- 13478613
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- NDL書誌ID
- 10755941
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
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