Cell type-specific post-transcriptional regulation of production of the potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose
Cell type-specific post-transcriptional regulation of production of the potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose
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DOI：
10.1074/jbc.m706435200
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发表时间：
2008-02-29
影响因子：
4.8
通讯作者：
Stenina, Olga I.
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Sanghamitra;Marinic, Tina E.;Stenina, Olga I.
高血糖是血管性糖尿病并发症发生的独立危险因素。糖尿病患者血管功能障碍表现为组织特异性；大血管系统受动脉粥样硬化病变的影响，微血管并发症被描述为“异常血管生成”：在同一患者中，一些组织（如视网膜新生血管）血管生成增加，而另一些组织（如皮肤）血管生成减少。调节血管对高血糖反应的分子细胞和组织特异性机制尚不清楚。血栓反应蛋白-1 （TSP-1）是一种有效的抗血管生成和促动脉粥样硬化蛋白，与几种血管性糖尿病并发症（动脉粥样硬化、肾病和心肌病）的发生有关。本研究考察了高糖对血小板反应蛋白-1生成的细胞类型特异性调节。我们之前报道了糖尿病动物大动脉中TSP-1的表达增加。mRNA和蛋白水平在高糖环境下上调。与大血管细胞不同，在微血管内皮细胞和视网膜色素上皮细胞（RPE）中，TSP-1蛋白水平在高葡萄糖的作用下显著降低。这种下调是转录后的；mRNA水平升高。原位杂交和免疫组化结果显示，糖尿病大鼠RPE组织中mRNA水平上调，蛋白水平降低。在微血管内皮细胞和RPE中，高葡萄糖对细胞类型特异性的TSP-1产生的转录后抑制是由TSP-1 mRNA的非翻译区域控制的，该区域调节TSP-1 mRNA与多体的偶联及其翻译。TSP-1的细胞特异性调控提示了糖尿病患者血管生成异常和TSP-1参与各种血管性糖尿病并发症发展的潜在机制。
Hyperglycemia is an independent risk factor for development of vascular diabetic complications. Vascular dysfunction in diabetics manifests in a tissue-specific manner; macrovasculature is affected by atherosclerotic lesions, and microvascular complications are described as "aberrant angiogenesis": in the same patient angiogenesis is increased in some tissues ( e. g. retinal neovascularization) and decreased in others ( e. g. in skin). Molecular cell- and tissue-specific mechanisms regulating the response of vasculature to hyperglycemia remain unclear. Thrombospondin-1 (TSP-1), a potent antiangiogenic and proatherogenic protein, has been implicated in the development of several vascular diabetic complications ( atherosclerosis, nephropathy, and cardiomyopathy). This study examines cell type-specific regulation of production of thrombospondin-1 by high glucose. We previously reported the increased expression of TSP-1 in the large arteries of diabetic animals. mRNA and protein levels were up- regulated in response to high glucose. Unlike in macrovascular cells, TSP-1 protein levels are dramatically decreased in response to high glucose in microvascular endothelial cells and retinal pigment epithelial cells (RPE). This down-regulation is post-transcriptional; mRNA levels are increased. In situ mRNA hybridization and immunohistochemistry revealed that the level of mRNA is up- regulated in RPE of diabetic rats, whereas the protein level is decreased. This cell type-specific post-transcriptional suppression of TSP-1 production in response to high glucose in microvascular endothelial cells and RPE is controlled by untranslated regions of TSP-1 mRNA that regulate coupling of TSP-1 mRNA to polysomes and its translation. The cell specific regulation of TSP-1 suggests a potential mechanism for the aberrant angiogenesis in diabetics and TSP-1 involvement in development of various vascular diabetic complications.