α1-antitrypsin protects β-cells from apoptosis
α1-antitrypsin protects β-cells from apoptosis
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DOI：
10.2337/db06-1273
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发表时间：
2007-05-01
期刊：
影响因子：
7.7
通讯作者：
Song, Sihong
中科院分区：
文献类型：
--
作者：
Zhang, Bin;Lu, Yuanqing;Song, Sihong
β-细胞凋亡似乎代表了1型糖尿病发病机制中的关键事件。先前的研究已经证明，丝氨酸蛋白酶抑制剂α 1-抗胰蛋白酶（AAT）的管理，防止1型糖尿病的发展NOD小鼠和胰岛移植物存活啮齿动物，但这种治疗效益的机制仍然很大程度上不清楚。在此，我们描述了新的发现，表明AAT显着减少细胞因子和链脲佐菌素（STZ）诱导的β细胞凋亡。特别是，当鼠胰岛素瘤细胞（MIN 6）暴露于肿瘤坏死因子-α时，观察到AAT（Prolastin，人）的强抗凋亡活性。在涉及STZ诱导的β细胞凋亡的第二个模型系统中，用AAT处理MIN 6细胞类似地诱导细胞活力的显著增加和凋亡的减少。重要的是，在两种模型系统中，用AAT处理完全消除了诱导的半胱天冬酶-3活性。就其在体内的活性而言，用AAT治疗C57 BL/6小鼠预防了STZ诱导的糖尿病，并且与体外分析一致，支持涉及破坏β细胞凋亡的机制的概念。这些结果为这种分子提出了一种新的生物学功能，并表明它可能代表了试图预防或逆转1型糖尿病的有效候选人。
beta-Cell apoptosis appears to represent a key event in the pathogenesis of type 1 diabetes. Previous studies have demonstrated that administration of the serine proteinase inhibitor al-antitrypsin (AAT) prevents type 1 diabetes development in NOD mice and prolongs islet allograft survival in rodents; yet the mechanisms underlying this therapeutic benefit remain largely unclear. Herein we describe novel findings indicating that AAT significantly reduces cytokine- and streptozotocin (STZ)-induced beta-cell apoptosis. Specifically, strong antiapoptotic activities for AAT (Prolastin, human) were observed when murine insulinoma cells (MIN6) were exposed to tumor necrosis factor-a. In a second model system involving STZ-induced beta-cell apoptosis, treatment of MIN6 cells with AAT similarly induced a significant increase in cellular viability and a reduction in apoptosis. Importantly, in both model systems, treatment with AAT completely abolished induced caspase-3 activity. In terms of its activities in vivo, treatment of C57BL/6 mice with AAT prevented STZ-induced diabetes and, in agreement with the in vitro analyses, supported the concept of a mechanism involving the disruption of beta-cell apoptosis. These results propose a novel biological function for this molecule and suggest it may represent an effective candidate for attempts seeking to prevent or reverse type 1 diabetes.