Apoptosis in hypoxic human pancreatic islets correlates with HIF-1α expression
Apoptosis in hypoxic human pancreatic islets correlates with HIF-1α expression
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DOI：
10.1096/fj.01-0403fje
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发表时间：
2002-03-01
期刊：
影响因子：
4.8
通讯作者：
Weber, M
中科院分区：
文献类型：
--
作者：
Moritz, W;Meier, F;Weber, M
为了实现胰岛素独立，1 型糖尿病患者需要移植至少两个供体胰腺，因为移植后早期会出现大量 β 细胞损失。许多描述新免疫抑制方案引入的研究表明，这种损失不仅是由于免疫事件，而且是由于非免疫因素。为了测试缺氧在多大程度上可能导致早期移植物丢失，我们分析了细胞凋亡事件的发生和缺氧诱导因子 1 (HIF-1) 的表达，HIF-1 是一种由氧依赖性 α 亚基和组成型 β 亚基组成的异二聚体转录因子。对人类和大鼠胰岛的组织学分析显示，早在缺氧暴露（1% O-2）后 6 小时就出现核固缩。此外，在分离的人胰岛的核心区域观察到对活化的 caspase-3 的免疫反应性。值得注意的是，这两种细胞凋亡标记物在形态上与 HIF-1α 免疫反应性重叠。在人和大鼠的胰岛以及几种小鼠 β 细胞系中检测到 HIF-1α mRNA。当暴露于缺氧时，小鼠胰岛素瘤细胞 (MIN6) 的 HIF-1α 蛋白水平增加，但其 mRNA 水平没有改变。总之，我们的数据提供了令人信服的证据，表明氧合作用减少是 β 细胞损失的重要原因，并表明 HIF-1α 蛋白水平是缺氧区域发生细胞凋亡的指标。这些观察结果表明，HIF-1 控制下的基因表达代表了改善移植胰岛植入的潜在治疗工具。
To become insulin independent, patients with type 1 diabetes mellitus require transplantation of at least two donor pancreata because of massive beta-cell loss in the early post-transplantation period. Many studies describing the introduction of new immunosuppressive protocols have shown that this loss is due to not only immunological events but also nonimmunological factors. To test to what extent hypoxia may contribute to early graft loss, we analyzed the occurrence of apoptotic events and the expression of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor consisting of an oxygen-dependent alpha subunit and a constitutive beta subunit. Histological analysis of human and rat islets revealed nuclear pyknosis as early as 6 h after hypoxic exposure (1% O-2). Moreover, immunoreactivity to activated caspase-3 was observed in the core region of isolated human islets. Of note, both of these markers of apoptosis topographically overlap with HIF-1alpha immunoreactivity. HIF-1alpha mRNA was detected in islets from human and rat as well as in several murine beta-cell lines. When exposed to hypoxia, mouse insulinoma cells (MIN6) had an increased HIF-1alpha protein level, whereas its mRNA level did not alter. In conclusion, our data provide convincing evidence that reduced oxygenation is an important cause of beta-cell loss and suggest that HIF-1alpha protein level is an indicator for hypoxic regions undergoing apoptotic cell death. These observations suggest that gene expression under the control of HIF-1 represents a potential therapeutic tool for improving engraftment of transplanted islets.