Selective Regulation of Heme Oxygenase-1 Expression and Function by Insulin through IRS1/Phosphoinositide 3-Kinase/Akt-2 Pathway
Selective Regulation of Heme Oxygenase-1 Expression and Function by Insulin through IRS1/Phosphoinositide 3-Kinase/Akt-2 Pathway
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DOI：
10.1074/jbc.m807036200
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发表时间：
2008-12-05
影响因子：
4.8
通讯作者：
King, George L.
中科院分区：
文献类型：
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作者：
Geraldes, Pedro;Yagi, Kunimasa;King, George L.
血红素加氧酶1（HO-1）是血管细胞中抗氧化剂和细胞保护剂的代表性介体，其对抗包括氧化剂在内的各种应激刺激。强化胰岛素治疗可以延缓糖尿病视网膜病变和其他血管病变的发生和进展，但关于胰岛素对血管细胞中抗凋亡和抗氧化分子如HO-1的调节知之甚少。玻璃体内注射或体外添加胰岛素增加HO-1蛋白在大鼠视网膜和培养的牛视网膜周细胞，视网膜内皮细胞，视网膜色素上皮细胞的表达。在牛视网膜周细胞中，胰岛素以时间和浓度依赖性方式诱导HO-1的mRNA和蛋白表达。使用HO-1启动子分析，荧光素酶报告基因分析表明，胰岛素诱导HO-1表达是由HO-1启动子基因中的额外响应元件介导的，该元件对抗氧化剂没有响应。胰岛素通过激活PI 3-kinase/Akt通路诱导HO-1 mRNA表达，而不影响ERK和p38 MAPK。通过腺病毒载体介导的内源性IRS 1、IRS 2和Akt显性负性基因的过表达或小干扰RNA转染Akt 1和Akt 2靶向基因，证实胰岛素选择性地通过IRS 1和Akt 2途径调节HO-1的表达。此外，胰岛素治疗通过IRS 1/PI 3 K/Akt 2/HO-1途径阻止了H2 O2诱导的NF-κ B和caspase-8活化和周细胞凋亡。总之，我们认为胰岛素的抗凋亡特性部分是通过IRS 1/PI 3 K/Akt 2激活在转录水平上增加HO-1表达介导的，这是胰岛素如何延缓糖尿病诱导的微血管并发症进展的一个潜在解释。
Heme oxygenase 1 (HO-1) is a representative mediator of antioxidants and cytoprotectants against various stress stimuli including oxidants in vascular cells. Intensive insulin treatment can delay the onset and progression of diabetic retinopathy and other vascularopathies, yet little is known about insulin regulation of anti-apoptotic and antioxidant molecules such as HO-1 in vascular cells. Intravitreous injection or in vitro addition of insulin increased HO-1 protein expression in rat retina and in cultured bovine retinal pericytes, retinal endothelial cells, and retinal pigment epithelial cells. In bovine retinal pericytes, insulin induced mRNA and protein expression of HO-1 in a time- and concentration-dependent manner. Using HO-1 promoter analysis, the luciferase reporter assay showed that induction of HO-1 expression by insulin is mediated by additional response elements in the ho-1 promoter gene, which was not responsive to antioxidants. Insulin-induced HO-1 mRNA expression through activation of PI3-kinase/Akt pathway without affecting ERK and p38 MAPK. Overexpression of an adenoviral vector of native IRS1, IRS2, and Akt dominant negative or small interfering RNA transfection of Akt1 and Akt2 targeted gene demonstrated that insulin regulated HO-1 expression via IRS1 and Akt2 pathway, selectively. Further, insulin treatment prevented H2O2-induced NF-kappa B and caspase-8 activation and apoptosis via the IRS1/PI3K/Akt2/HO-1 pathway in the pericytes. In conclusion, we suggest that the anti-apoptotic properties of insulin are mediated partly by increasing HO-1 expression at transcriptional level via IRS1/PI3K/Akt2 activation, a potential explanation for how insulin is retarding the progression of microvascular complications induced by diabetes.