Endothelial cell calpain as a critical modulator of angiogenesis.
Endothelial cell calpain as a critical modulator of angiogenesis.
复制标题
内皮细胞钙蛋白酶作为血管生成的关键调节剂。
DOI：
10.1016/j.bbadis.2017.03.021
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Cai H
中科院分区：
文献类型：
--
作者：
Zhang Y;Liu NM;Wang Y;Youn JY;Cai H
钙蛋白酶是钙依赖性非溶酶体半胱氨酸蛋白酶的一个家族。特别是内皮细胞中的钙蛋白酶在血管生成中起重要作用。研究表明，钙蛋白酶活性可以通过生长因子，主要是血管内皮生长因子（VEGF）在内皮细胞中增加。VEGF/VEGFR2诱导calpain 2依赖性的PI3K/AMPK/Akt/eNOS通路激活，从而产生一氧化氮和生理性血管生成。在肿瘤血管生成等病理条件下，内皮细胞可被缺氧激活。本文综述了钙蛋白酶活性的分子调控机制，以及新发现的钙蛋白酶在生理性血管生成、病理性肿瘤血管生成、糖尿病伤口愈合、视网膜病变和动脉粥样硬化等方面的作用和下游信号事件，这些都与钙蛋白酶活性增加有关。进一步讨论包括在不同病理环境下通过操纵钙蛋白酶表达/活性来调节血管生成的不同策略。通过调节calpain和calpain依赖的信号机制，靶向限制癌症血管生成和靶向促进糖尿病伤口愈合的血管生成具有重要的翻译潜力。新兴的组织特异性靶向、环境依赖性靶向和基因组靶向编辑策略可能会成为通过钙蛋白酶途径靶向操纵血管生成的有效方案，用于包括肿瘤血管生成衰减和糖尿病血管生成增强在内的差异化治疗。
Calpains are a family of calcium-dependent non-lysosomal cysteine proteases. In particular, calpains residing in the endothelial cells play important roles in angiogenesis. It has been shown that calpain activity can be increased in endothelial cells by growth factors, primarily vascular endothelial growth factor (VEGF). VEGF/VEGFR2 induces calpain 2 dependent activation of PI3K/AMPK/Akt/eNOS pathway, and consequent nitric oxide production and physiological angiogenesis. Under pathological conditions such as tumor angiogenesis, endothelial calpains can be activated by hypoxia. This review focuses on the molecular regulatory mechanisms of calpain activation, and the newly identified mechanistic roles and downstream signaling events of calpains in physiological angiogenesis, and in the conditions of pathological tumor angiogenesis and diabetic wound healing, as well as retinopathy and atherosclerosis that are also associated with an increase in calpain activity. Further discussed include the differential strategies of modulating angiogenesis through manipulating calpain expression/activity in different pathological settings. Targeted limitation of angiogenesis in cancer and targeted promotion of angiogenesis in diabetic wound healing via modulations of calpains and calpain-dependent signaling mechanisms are of significant translational potential. Emerging strategies of tissue-specific targeting, environment-dependent targeting, and genome-targeted editing may turn out to be effective regimens for targeted manipulation of angiogenesis through calpain pathways, for differential treatments including both attenuation of tumor angiogenesis and potentiation of diabetic angiogenesis.
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