Mechanisms Underlying the Anti-inflammatory Effects of the Ca2+/Calmodulin Antagonist CV-159 in Cultured Vascular Smooth Muscle Cells

DOI Web Site 被引用文献1件 参考文献71件
  • Usui Tatsuya
    Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
  • Yamawaki Hideyuki
    Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
  • Kamibayashi Masato
    Kyoto Pharmaceutical University, Japan
  • Okada Muneyoshi
    Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan
  • Hara Yukio
    Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Japan

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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.

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