Calcitonin gene-related peptide receptor activation by receptor activity-modifying protein-1 gene transfer to vascular smooth muscle cells.
Calcitonin gene-related peptide receptor activation by receptor activity-modifying protein-1 gene transfer to vascular smooth muscle cells.
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DOI：
10.1210/en.2005-0918
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发表时间：
2006-04
期刊：
影响因子：
4.8
通讯作者：
Zhongmin Zhang;I. Dickerson;A. Russo
中科院分区：
文献类型：
--
作者：
Zhongmin Zhang;I. Dickerson;A. Russo
神经肽降钙素基因相关肽（CGRP）是一种有效的血管扩张剂，在心血管系统中起保护作用。CGRP的受体是G蛋白偶联降钙素样受体和专性受体活性修饰蛋白-1（RAMP 1）的不寻常的复合物。在这份报告中，我们提供的第一个证据表明，RAMP 1是血管平滑肌细胞的速率限制。虽然培养的大鼠主动脉平滑肌细胞表达降钙素样受体和RAMP 1，我们发现CGRP不是一个有效的受体激活剂。通过腺病毒基因转移过表达RAMP 1后，CGRP诱导的cAMP产生显著增加，EC（50）降低75倍，最大反应增加1.5倍。在三种不同的范例中观察到这种受体活性增加的生物学后果。首先，RAMP 1基因转移导致CGRP依赖性细胞增殖减少。其次，RAMP 1和CGRP治疗导致3倍以上的自由基诱导的细胞数量减少。最后，RAMP 1基因转移导致5倍CGRP依赖性增加的末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记阳性凋亡细胞血清撤出后。这些作用的机制涉及cAMP依赖性途径。我们认为，RAMP 1基因转移可能是一种有效的策略，增加CGRP诱导的减少主动脉成形术后再狭窄的有效性。
The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator that plays a protective role in the cardiovascular system. The receptor for CGRP is an unusual complex of the G protein-coupled calcitonin-like receptor and an obligate receptor activity modifying protein-1 (RAMP1). In this report we provide the first evidence that RAMP1 is rate limiting in vascular smooth muscle cells. Although cultured rat aorta smooth muscle cells express calcitonin like-receptor and RAMP1, we found that CGRP is not a potent activator of the receptor. After overexpression of RAMP1 by adenoviral gene transfer, there was a striking increase in CGRP-induced production of cAMP, with a 75-fold decrease in the EC(50) and a 1.5-fold increase in the maximal response. The biological consequence of this increased receptor activity was observed in three different paradigms. First, RAMP1 gene transfer caused a CGRP-dependent decrease in cell proliferation. Second, RAMP1 and CGRP treatment led to a 3-fold greater free radical-induced reduction in cell number. Finally, RAMP1 gene transfer resulted in a 5-fold CGRP-dependent increase in terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling-positive apoptotic cells upon serum withdrawal. The mechanisms underlying these effects involved cAMP-dependent pathways. We propose that RAMP1 gene transfer may be an effective strategy for increasing the effectiveness of CGRP-induced decrease in restenosis after aortic angioplasty.