Hyperglycemia induces apoptosis of human pancreatic islet endothelial cells - Effects of pravastatin on the Akt survival pathway
Hyperglycemia induces apoptosis of human pancreatic islet endothelial cells - Effects of pravastatin on the Akt survival pathway
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DOI：
10.2353/ajpath.2008.080238
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发表时间：
2008-08-01
影响因子：
6
通讯作者：
Zanone, Maria M.
中科院分区：
文献类型：
--
作者：
Favaro, Enrica;Miceli, Ilaria;Zanone, Maria M.
胰岛微内皮细胞和β细胞表现出相互依赖的物理和功能关系。在这项研究中，我们分析了慢性高血糖对人胰岛微内皮细胞的影响，以及磷脂酰肌醇3-激酶/Akt和nephrin通路、白细胞介素-1 β和一氧化氮的产生。此外，研究了3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂是否可以逆转对高葡萄糖条件的反应。与正常血糖细胞相比，高血糖条件（28 mmol/L葡萄糖）下培养的纯化胰岛微内皮细胞的增殖能力下降（从2天后的12.7%降至30天后的47.7%，P < 0.05）。与此同时，细胞凋亡从高糖培养2天后的7%逐渐增加到30天后的79%（P < 0.05），并伴随着caspase-3活性的早期增加。间歇性高血糖比持续性高血糖诱导更大的细胞凋亡。细胞凋亡伴随着p-Akt/Akt比值的降低和nephrin酪氨酸磷酸化的抑制。普伐他汀（1 μ mol/L）可减少高糖或氧化LDL诱导的细胞凋亡，增加Akt磷酸化。高血压显著增加促炎细胞因子白细胞介素-1 β的产生，并刺激诱导型一氧化氮合酶的表达和一氧化氮的产生，可能与β细胞的质量和功能有关。因此，慢性高血糖症通过抑制丝氨酸-苏氨酸激酶Akt途径降低胰岛微内皮细胞存活率，普伐他汀对该途径的作用代表了改善胰岛血管形成和间接改善胰岛功能的潜在工具。
Pancreatic islet microendothelium and beta cells exhibit an interdependent physical and functional relationship. in this study, we analyzed the effect of chronic hyperglycemia on human pancreatic islet microendothelial cells as well as the involvement of the phosphatidylinositol 3-kinase/Akt and nephrin pathways, interleukin-1 beta, and nitric oxide production. In addition, whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can reverse the response to high-glucose conditions was investigated. Proliferation of purified islet microendothelial cells cultured under hyperglycemic conditions (28 mmol/L glucose) decreased compared to that of normoglycemic cells (from 12.7% after 2 days to 47.7% after 30 days, P < 0.05). in parallel, apoptosis progressively increased from 7% after 2 days to 79% after 30 days in high glucose (P < 0.05) concomitant with an early increase of caspase-3 activity. intermittent hyperglycemia induced greater apoptosis than sustained hyperglycemia. Apoptosis was accompanied by a reduced p-Akt/Akt ratio and inhibition of nephrin tyrosine phosphorylation. Pravastatin (1 mu mol/L) decreased apoptosis induced by high glucose or oxidized LDL and increased Akt phosphorylation. Hyperglycemia significantly increased the production of the proinflammatory cytokine interleukin-1 beta and stimulated the expression of inducible nitric oxide synthase and the production of nitric oxide, possibly relevant to beta cell mass and function. Thus, chronic hyperglycemia reduces islet microendothelial cell survival by inhibiting the serine-threonine kinase Akt pathway, and the effect of pravastatin on this pathway represents a potential tool to improve islet vascularization and, indirectly, islet Function.