INTEGRIN OVEREXPRESSION INDUCED BY HIGH GLUCOSE AND BY HUMAN DIABETES - POTENTIAL PATHWAY TO CELL DYSFUNCTION IN DIABETIC MICROANGIOPATHY
INTEGRIN OVEREXPRESSION INDUCED BY HIGH GLUCOSE AND BY HUMAN DIABETES - POTENTIAL PATHWAY TO CELL DYSFUNCTION IN DIABETIC MICROANGIOPATHY
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DOI：
10.1073/pnas.90.20.9640
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发表时间：
1993-10-15
影响因子：
11.1
通讯作者：
LORENZI, M
中科院分区：
文献类型：
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作者：
ROTH, T;PODESTA, F;LORENZI, M
导致糖尿病微血管病变的无细胞非灌注毛细血管的过程的性质仍然未知。由于这些毛细血管表现为基底膜增厚，我们询问在糖尿病中引起过量细胞外基质沉积的过程是否在损害细胞更新的方向上改变了细胞-基质相互作用。在44个人脐静脉内皮细胞分离株中，我们观察到高葡萄糖浓度（30 mM）诱导编码纤连蛋白和纤连蛋白特异性整合素受体α 5 β 1以及同源蛋白的mRNA水平的协同增加。整合素亚基α 3的表达，纤维连接蛋白，层粘连蛋白和胶原蛋白的α 3 β 1多特异性受体的组成部分，也上调高糖。整合素的过度表达与细胞对外源性纤连蛋白和层粘连蛋白以及复杂基质的附着增加相关。此外，细胞表现出更坚定的稳态粘附到自己的基质。为了将这些体外观察结果与人类糖尿病视网膜病变事件相关联，我们测量了10例8.2 +/- 1.6（平均+/- SE）年糖尿病患者和10例年龄和性别匹配的非糖尿病对照的视网膜胰蛋白酶抑制剂中的整合素水平。糖尿病患者微血管β 1整合素的免疫染色增强（P = 0.025），与对照微血管相比。这些数据表明，高葡萄糖和糖尿病增加整合素的表达，从而改变血管内皮细胞与其基底膜的相互作用，在更坚定的细胞-基质粘附的方向。这可能会损害对再内皮化过程至关重要的迁移和复制，并导致微血管闭塞。
The nature of the process leading to the acellular nonperfused capillaries of diabetic microangiopathy remains unknown. Because these capillaries manifest thickened basement membranes, we asked whether the process causing deposition of excess extracellular matrix in diabetes modifies cell-matrix interactions in a direction that would compromise cell renewal. In 44 individual isolates of human umbilical vein endothelial cells we observed that high glucose concentrations (30 mM) induce coordinate increases in the levels of mRNAs encoding fibronectin and the fibronectin-specific integrin receptor alpha5beta1 as well as in the cognate proteins. Expression of the integrin subunit alpha3, component of the alpha3beta1 polyspecific receptor for fibronectin, laminin, and collagen, was also up-regulated by high glucose. Overexpression of integrins correlated with increased cell attachment to exogenous fibronectin and laminin as well as to complex matrix. Moreover, cells exhibited firmer steady-state adhesion to their own matrix. To correlate these in vitro observations with events in human diabetic retinopathy we measured integrin levels in retinal trypsin digests prepared from 10 patients with 8.2 +/- 1.6 (mean +/- SE) years of diabetes and 10 age- and sex-matched nondiabetic controls. Microvessels of diabetic patients showed increased immunostaining for beta1 integrin (P = 0.025) when compared with control microvessels. These data show that high glucose and diabetes increase integrin expression and thus alter the interaction of vascular endothelial cells with their basement membranes in the direction of firmer cell-matrix adhesion. This could compromise the migration and replication critical to the reendothelialization process and contribute to microvascular occlusion.