Chromogranin A protects vessels against tumor necrosis factor α-induced vascular leakage
Chromogranin A protects vessels against tumor necrosis factor α-induced vascular leakage
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DOI：
10.1096/fj.03-0922fje
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发表时间：
2004-01-01
期刊：
影响因子：
4.8
通讯作者：
Corti, A
中科院分区：
文献类型：
--
作者：
Ferrero, E;Scabini, S;Corti, A
在神经内分泌肿瘤或心力衰竭患者的血液中检测到循环嗜铬粒蛋白 A (CgA) 水平升高，CgA 是一种储存在许多神经内分泌细胞和神经元的分泌颗粒中的蛋白质。 CgA 分泌增加的病理生理学作用尚不清楚。使用携带皮下肿瘤的小鼠进行基因工程改造，在循环中分泌 CgA，我们发现这种蛋白质的血液水平增加可以防止肿瘤坏死因子-α 引起的血管渗漏。 (TNF) 存在于肝静脉系统中。对正常小鼠施用 CgA 片段进行的结构活性研究表明，活性位点位于 CgA 的残基 7-57 内。因此，针对残基53-57的抗CgA抗体抑制内源产生或外源施用的循环CgA对肝血管的作用。作用机制研究表明，CgA 以间接方式抑制 TNF 诱导的 VE-钙粘蛋白下调和培养内皮细胞的屏障改变。在体外渗透性测定中，其他效应物，例如凝血酶和血管内皮生长因子，被 CgA N 末端片段部分抑制。这些发现表明，在以 TNF 和 CgA 产生增加为特征的病理状况（例如癌症或心力衰竭）中，循环 CgA 可以帮助调节内皮屏障功能并保护血管免受 TNF 诱导的血浆渗漏。
Elevated levels of circulating chromogranin A (CgA), a protein stored in the secretory granules of many neuroendocrine cells and neurons, have been detected in the blood of patients with neuroendocrine tumors or heart failure. The pathophysiological role of increased secretion of CgA is unknown. Using mice bearing subcutaneous tumors genetically engineered to secrete CgA in circulation, we have found that increased blood levels of this protein prevent vascular leakage induced by tumor necrosis factor-alpha. (TNF) in the liver venous system. Structure-activity studies, carried out with CgA fragments administered to normal mice, showed that an active site is located within residues 7-57 of CgA. Accordingly, an anti-CgA antibody directed to residues 53-57 inhibited the effect of circulating CgA, either endogenously produced or exogenously administered, on liver vessels. Studies of the mechanism of action showed that CgA inhibits TNF-induced VE-cadherin down-regulation and barrier alteration of cultured endothelial cells, in an indirect manner. Other effectors, such as thrombin and vascular endothelial growth factor were partially inhibited by CgA N-terminal fragments in in vitro permeability assays. These findings suggest that circulating CgA could help regulate the endothelial barrier function and to protect vessels against TNF-induced plasma leakage in pathological conditions characterized by increased production of TNF and CgA, such as cancer or heart failure.