Voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by angiotensin II in mice

被引:13
作者
Nishida, Motohiro [1 ]
Ishikawa, Tatsuya [2 ]
Saiki, Shota [1 ]
Sunggip, Caroline [1 ]
Aritomi, Shizuka [2 ]
Harada, Eri [2 ]
Kuwahara, Koichiro [3 ]
Hirano, Katsuya [4 ]
Mori, Yasuo [5 ,6 ]
Kim-Mitsuyama, Shokei [7 ]
机构
[1] Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Drug Discovery & Evolut, Higashi Ku, Fukuoka 8128582, Japan
[2] Ajinomoto Pharmaceut Co Ltd, Chuo Ku, Tokyo 1040042, Japan
[3] Kyoto Univ, Grad Sch Med, Dept Med & Clin Sci, Kyoto, Japan
[4] Kyushu Univ, Div Mol Cardiol, Angiocardiol Res Inst, Grad Sch Med Sci, Fukuoka 812, Japan
[5] Kyoto Univ, Grad Sch Environm Studies, Lab Environm Syst Biol, Kyoto, Japan
[6] Kyoto Univ, Grad Sch Engn, Mol Biol Lab, Dept Synthet Chem & Biol Chem, Kyoto, Japan
[7] Kumamoto Univ, Grad Sch Med Sci, Dept Pharmacol & Mol Therapeut, Kumamoto 8608556, Japan
关键词
N-type Ca2+ channel; Cilnidipine; Reactive oxygen species; Hypertension; Vascular relaxation; BLOCKER CILNIDIPINE; V; 2.2; RECEPTOR; NOREPINEPHRINE; HYPERTENSION; ANTAGONIST; AMLODIPINE; RELEASE; SYSTEM;
D O I
10.1016/j.bbrc.2013.03.040
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
N-type voltage-dependent Ca(2+)channels (VDCCs), expressed predominantly in the nervous system, play pivotal roles in sympathetic regulation of the circulatory system. Although N-type VDCCs are also reportedly expressed in the vasculature, their pathophysiological role is obscure. We demonstrated that oxidative stress-related endothelial dysfunction induced by angiotensin (Ang) II is suppressed in mice lacking the N-type VDCC alpha(1B) subunit (Ca-v 2.2). Impairment of endothelium-dependent relaxation of the thoracic aorta observed following Ang II treatment in wild-type (WT) mice was significantly attenuated in the Ang II-treated Ca-v 2.2-deficient mice, despite the comparable increase of the blood pressure in the two groups of mice. The thoracic aorta of the Ca-v 2.2-deficient mice showed a smaller positive area of oxidative stress markers as compared to the WT mice. The Ang II-induced endothelial dysfunction was also suppressed by cilnidipine, an L/N-type VDCC blocker, but not by amlodipine, an L-type VDCC blocker; however, this unique effect of cilnidipine was completely abolished in the Ca-v 2.2-deficient mice. Furthermore, selective inhibition of N-type VDCCs by omega-conotoxin GVIA dramatically suppressed the production of reactive oxygen species (ROS) as well as agonist-induced Ca2+ influx in the vascular endothelial cells. These results suggest that N-type VDCCs expressed in the vascular endothelial cells contribute to ROS production and endothelial dysfunction observed in Ang II-treated hypertensive mice. (c) 2013 Elsevier Inc. All rights reserved.
引用
收藏
页码:210 / 216
页数:7
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