人源性激肽释放酶结合蛋白与内皮细胞功能

Kallistatin and endothelial cell activity

人源性激肽释放酶结合蛋白(Kallistatin,Kal)是一种负性急性期内源性蛋白,与多种内皮相关性生理和病理过程密切相关,如血管生成及损伤修复、炎症、心功能不全、肾损伤、糖尿病等。炎症和氧化应激可引起内皮功能障碍,而Kal可抑制肿瘤坏死因子α引起的内皮细胞活化,通过KLF4-eNOS、PI3K-AKT-eNOS和AKT-FOXO1等信号通路,增加内皮细胞NO合酶的表达和NO生成,抑制内皮细胞损伤和凋亡。动物实验显示,Kal表达增加可减弱氧化应激诱导的细胞凋亡和器官损伤。基于内皮细胞所处的状态或来源,如健康或损伤情况,成熟内皮细胞或内皮祖细胞,Kal的作用可能有所区别。内皮细胞是参与肿瘤生长与转移的关键因素已达成共识,但肿瘤新生血管形成的机制尚待确认。Kal可诱导肿瘤内皮细胞凋亡,抑制肿瘤新生血管生成和肿瘤生长的能力已被证实。临床前研究结果表明,Kal具有多种药理作用,对氧化应激相关性疾病,特别是肿瘤治疗具有应用前景,但其药理作用的分子机制仍需深入探讨。

Kallistatin（Kal） is a negative acute phase endogenous protein which is closely related with a variety of endothelium associated physiological and pathological processes,such as angiogenesis,blood vessel injury recovery,heart failure,kidney damage,diabetes and so on.Kal increases endothelial NO synthase expression and NO production,inhibits endothelial cell apoptosis and organ damage caused by inflammation and oxidative stress,through activation of KLF4-eNOS,PI3K-AKT-eNOS and AKT-FOXO1 signaling pathways,and prevens TNF-α mediated endothelial activation.Animal experiments showed increased Kal expression in vivo can reduce oxidative stress-induced cell apoptosis and organ damage.Kal may play different roles with different kinds of endothelial cells,depending on their phenotypes and conditions,such as mature or progenitor cells,healthy or diseased.It is established that tumor growth and metastasis are regulated in part by endothelial cells within the tumor microenvironment,and yet,the exact mechanisms of neovascularization in tumor are less well understood.Numerous studies demonstrated that Kal can inhibit tumor angiogenesis,growth and metastasis effectively.Although the preclinical results suggest that Kal has pleiotropic pharmacological effects and represents a promising strategy for the treatment of oxidative stress related diseases,especially cancer,detailed molecular mechanism still needs to be explored before clinic application.