INSULIN STIMULATES PRODUCTION AND SECRETION OF ENDOTHELIN FROM BOVINE ENDOTHELIAL-CELLS
INSULIN STIMULATES PRODUCTION AND SECRETION OF ENDOTHELIN FROM BOVINE ENDOTHELIAL-CELLS
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DOI：
10.2337/diabetes.42.2.351
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发表时间：
1993-02-01
期刊：
影响因子：
7.7
通讯作者：
FRANK, HJL
中科院分区：
文献类型：
--
作者：
HU, RM;LEVIN, ER;FRANK, HJL
内皮素是一种由内皮细胞分泌的血管收缩多肽，被认为在各种形式的血管疾病中发挥作用。众所周知，糖尿病与加速的动脉粥样硬化和微血管损伤有关。尽管血管损伤的基础是多因素的，但高胰岛素血症被认为是由一种未知的机制造成的。在这项研究中，我们试图确定胰岛素是否刺激ET-1的产生和分泌，作为高胰岛素血症和血管疾病关联的可能基础。我们发现胰岛素显著刺激培养的BAEC表达和分泌ET-1，并增加BBCEC中ET-1mRNA的表达。胰岛素可诱导BAEC中ET-1mRNA的表达，且呈剂量依赖关系。核径流研究表明，mRNA的增加是转录增加的结果。胰岛素刺激BAEC分泌ET-1的作用呈剂量依赖性，生理浓度(10~(-9)M)时，ET-1的分泌增加一倍，从孵育1h开始，持续至24 h。酪氨酸激酶抑制剂金雀异黄素可显著抑制胰岛素诱导的ET-1mRNA和ET-1蛋白分泌的增加。这种刺激可能通过胰岛素受体发生，因为IGF-1对这些细胞的ET-1基因表达或分泌没有影响。放线菌素D可抑制胰岛素对ET-1mRNA的刺激作用，而放线菌酮对胰岛素的作用有超强诱导作用。皮下植入胰岛素颗粒10天的大鼠血浆ET水平显著升高，证实了体内胰岛素的刺激作用，无论是糖尿病啮齿动物还是正常啮齿动物。本研究提示，高胰岛素血症可诱导血管平滑肌细胞产生和分泌内源性血管收缩因子和有丝分裂原ET-1。这种相互作用可能是高胰岛素血症糖尿病状态血管病变增加的基础。
Endothelin, a vasoconstrictor peptide secreted from endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with accelerated atherosclerosis and microvascular damage. Although the basis for the vessel insult is multifactorial, hyperinsulinemia is thought to contribute by an unknown mechanism. In this study, we sought to determine whether insulin stimulates the production and secretion of ET-1 as a possible basis for the association of hyperinsulinemia and vascular disease. We demonstrated that insulin significantly stimulates the gene expression and secretion of ET-1 from cultured BAEC, and that insulin increases ET-1 mRNA expressed in BBCEC. Insulin caused a maximal twofold inducement above control ET-1 mRNA expression in a dose-related fashion in BAEC. The increased mRNA resulted from increased transcription, as determined by nuclear run-off studies. Increased ET-1 mRNA was seen after 4 h of incubation with insulin: the peak occurred at 6-8 h and persisted for 24 h. Insulin caused as much as a fourfold stimulation of ET-1 secretion from BAEC in a dose-related fashion, including a twofold increase at a physiological concentration (10(-9) M): The increase began at 1 h of incubation and continued for the entire 24-h incubation period. The insulin-induced increases in both ET-1 mRNA and ET-1 protein secretion were significantly attenuated by genistein, a tyrosine kinase inhibitor. This stimulation probably occurred through the insulin receptor, because IGF-1 had no effect on ET-1 gene expression or secretion from these cells. Actinomycin-D inhibited the stimulation of ET-1 mRNA by insulin, whereas cycloheximide caused a superinducement of insulin's effect. Rats implanted with subcutaneous insulin pellets for 10 days had markedly elevated plasma ET levels, confirming a stimulatory role for insulin in vivo, in both diabetic and normal rodents. This study suggests that circulating hyperinsulinemia might induce the production and secretion of ET-1, a powerful endogenous vasoconstrictor and mitogen lor the vascular smooth muscle cell. This interaction could underlie the increased vascular disease characteristic of hyperinsulinemic diabetic states.