Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury.
Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury.
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DOI：
10.1016/j.yjmcc.2013.02.002
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发表时间：
2013-06
影响因子：
5
通讯作者：
Lei Yang;T. Sakurai;Akiko Kamiyoshi;Yuka Ichikawa-Shindo;Hisaka Kawate;T. Yoshizawa;T. Koyama;Yasuhiro Iesato;Ryuichi Uetake;Akihiro Yamauchi;Megumu Tanaka;Yuichi Toriyama;Kyoko Igarashi;T. Shindo
中科院分区：
文献类型：
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作者：
Lei Yang;T. Sakurai;Akiko Kamiyoshi;Yuka Ichikawa-Shindo;Hisaka Kawate;T. Yoshizawa;T. Koyama;Yasuhiro Iesato;Ryuichi Uetake;Akihiro Yamauchi;Megumu Tanaka;Yuichi Toriyama;Kyoko Igarashi;T. Shindo
新生内膜增生是动脉粥样硬化和经皮冠状动脉介入治疗后再狭窄的主要病变。降钙素基因相关肽（CGRP）是由降钙素/CGRP基因的初级转录物的选择性剪接产生的。CGRP最初被鉴定为强血管舒张神经肽，现在已知是广泛分布于各种器官和组织中的多效性肽。我们的目的是研究CGRP作为内源性血管保护分子的可能性。我们在野生型和CGRP敲除（CGRP-/-）小鼠中比较了CGRP缺乏对导丝诱导的血管损伤后新生内膜形成的影响。我们发现，CGRP−/−小鼠血管损伤后新生内膜形成显著增强，这也表现出更高程度的氧化应激，表现为一氧化氮合酶表达减少，p47 phox表达增加，4 HNE水平升高，以及巨噬细胞浸润增加。此外，CGRP缺乏导致新生内膜内血管平滑肌细胞（VSMC）增殖增加。相比之下，骨髓来源的细胞对CGRP−/−小鼠的新生内膜形成几乎没有影响。体外分析显示CGRP处理抑制VSMC增殖、迁移和ERK 1/2活性。这些结果清楚地表明，内源性CGRP抑制血管损伤诱导的氧化应激和VSMC增殖。CGRP作为一种血管保护分子，可能成为心血管疾病治疗的重要靶点。
Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene. Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule. We compared the effect of CGRP deficiency on neointimal formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP−/−) mice. We found that neointimal formation after vascular injury was markedly enhanced in CGRP−/− mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointimal formation in CGRP−/−mice. In vitro analysis showed that CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease.