Expression of genes related to the extracellular matrix in human endothelial cells. Differential modulation by elevated glucose concentrations, phorbol esters, and cAMP.
Expression of genes related to the extracellular matrix in human endothelial cells. Differential modulation by elevated glucose concentrations, phorbol esters, and cAMP.
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DOI：
10.1016/s0021-9258(18)98674-6
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发表时间：
1991-08
期刊：
影响因子：
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通讯作者：
E. Cagliero;T. Roth;S. Roy;M. Maiello;M. Lorenzi
中科院分区：
文献类型：
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作者：
E. Cagliero;T. Roth;S. Roy;M. Maiello;M. Lorenzi
为了确定糖尿病血管病变基底膜增厚的原因和机制，我们检测了高糖(30 MM)对细胞外基质组成和周转相关基因表达的影响，并研究了高糖诱导的变化是否通过蛋白激酶C或A的激活来模拟和维持。在人脐静脉内皮细胞中，高糖使纤维连接蛋白、IV型胶原、组织纤溶酶原激活物(TPA)和纤溶酶原激活物抑制物1(PAI-1)的mRNA水平增加2倍，但不影响IV型和间质胶原酶的表达。佛波酯的急性处理导致IV型胶原、tPA、PAI-1和间质胶原酶mRNAs的增加，而IV型胶原酶的mRNAs水平反而被抑制到对照组的50%。长时间接触佛波醇酯(48h)后，纤维连接蛋白和PAI-1的mRNAs也受到抑制。细胞内cAMP的升高导致纤维连接蛋白和IV型胶原酶的过度表达，并增强佛波酯对IV型胶原、tPA和间质胶原酶表达的影响。高糖诱导的mRNA改变发生在没有蛋白激酶C激活或cAMP升高的情况下。这些研究表明，除了蛋白激酶C或A的激活以外，其他事件将环境高血糖与内皮细胞基因表达的变化联系起来，这可能是导致糖尿病血管病变的原因之一。
To identify agents and mechanisms responsible for the thickened basement membranes characteristic of diabetic angiopathy we examined the effects of high glucose (30 mM) on the expression of genes related to extracellular matrix composition and turnover and investigated whether the changes induced by high glucose were mimicked and sustained by activation of protein kinase C or A. In human umbilical vein endothelial cells high glucose increased fibronectin, collagen IV, tissue plasminogen activator (tPA), and plasminogen activator-inhibitor 1 (PAI-1) mRNA levels 2-fold but did not affect type IV and interstitial collagenase expression. Acute treatment with phorbol esters resulted in increased collagen IV, tPA, PAI-1, and interstitial collagenase mRNAs; the type IV collagenase mRNA levels were instead suppressed to 50% of control. Upon longer exposure to phorbol esters (48 h) suppression of fibronectin and PAI-1 mRNAs also occurred. Intracellular elevation of cAMP led to over-expression of fibronectin and type IV collagenase and potentiated the effects of phorbol esters on collagen IV, tPA, and interstitial collagenase expression. The mRNA changes induced by high glucose occurred in the absence of protein kinase C activation or cAMP elevation. These studies indicate that events other than activation of protein kinase C or A bridge high ambient glucose to changes in endothelial cell gene expression that may contribute to diabetic angiopathy.