Pandolfi A, Iacoviello L, Capani F, Vitacolonna E, Donati M B, Consoli A
Istituto di Fisiopatologia Medica, University of Chieti, Italy.
Diabetologia. 1996 Dec;39(12):1425-31. doi: 10.1007/s001250050594.
Hyperglycaemia and hyperinsulinaemia have both been related to accelerated atherosclerosis in non-insulin-dependent diabetes mellitus (NIDDM). Plasma fibrinolytic potential is reduced in NIDDM and it is known that glucose and insulin can modulate plasminogen activator inhibitor (PAI-1) and tissue-plasminogen activator (t-PA) secretion and can therefore regulate local fibrinolysis. Vascular smooth muscle cells (vSMC) play an important role in the development of atherosclerotic lesions; however, the role of insulin and glucose in regulating PAI-1 and t-PA production in vSMC is presently not known. Therefore, we cultured arterial vSMC explanted from human umbilical cords and exposed them to increasing concentrations of glucose (5, 12, 20, 27, 35 mmol/l) or insulin (0.1, 0.5, 1, 10 nmol/l) in a serum free medium. After 24 h, PAI-1 and t-PA antigens and activity were evaluated in the culture medium; in cells exposed to 20 mmol/l glucose and to 0.5 nmol/l insulin PAI-1 gene expression was also evaluated. An increase in PAI-1 antigen was observed at each glucose concentration (by 138, 169, 251 and 357% as compared to 5 mmol/l glucose) which was paralleled by an increase in PAI-1 activity. t-PA concentration was also increased by glucose but its activity was sharply reduced. An increase in PAI-1 antigen was detected at each insulin level (by 121, 128, 156 and 300% as compared to no insulin). PAI-1 activity was slightly increased at the lowest insulin concentrations but markedly increased by 10 nmol/l insulin. t-PA antigen was also increased by insulin; however, its activity was markedly reduced at each concentration. As compared to control cells, PAI-1 mRNA was increased by 2.5 and 2.0 fold by 20 mmol/l glucose and 0.5 nmol/l insulin, respectively. We conclude that in human vSMC both glucose and insulin can affect the fibrinolytic balance so as to reduce fibrinolytic potential. This might contribute to decreased local fibrinolysis and thereby might accelerate the atherothrombotic process in NIDDM subjects.
高血糖症和高胰岛素血症均与非胰岛素依赖型糖尿病（NIDDM）中动脉粥样硬化的加速发展有关。NIDDM患者的血浆纤溶潜力降低，并且已知葡萄糖和胰岛素可调节纤溶酶原激活物抑制剂（PAI - 1）和组织纤溶酶原激活物（t - PA）的分泌，因此能够调节局部纤溶作用。血管平滑肌细胞（vSMC）在动脉粥样硬化病变的发展中起重要作用；然而，胰岛素和葡萄糖在调节vSMC中PAI - 1和t - PA产生方面的作用目前尚不清楚。因此，我们培养了从人脐带中取出的动脉vSMC，并在无血清培养基中将它们暴露于浓度不断增加的葡萄糖（5、12、20、27、35 mmol/l）或胰岛素（0.1、0.5、1、10 nmol/l）中。24小时后，评估培养基中PAI - 1和t - PA的抗原及活性；对于暴露于20 mmol/l葡萄糖和0.5 nmol/l胰岛素的细胞，还评估了PAI - 1基因表达。在每个葡萄糖浓度下均观察到PAI - 1抗原增加（与5 mmol/l葡萄糖相比，分别增加了138%、169%、251%和357%），同时PAI - 1活性也增加。葡萄糖也使t - PA浓度增加，但其活性急剧降低。在每个胰岛素水平均检测到PAI - 1抗原增加（与无胰岛素相比，分别增加了121%、128%、156%和300%）。在最低胰岛素浓度下，PAI - 1活性略有增加，但在10 nmol/l胰岛素时显著增加。胰岛素也使t - PA抗原增加；然而，其活性在每个浓度下均显著降低。与对照细胞相比，20 mmol/l葡萄糖和0.5 nmol/l胰岛素分别使PAI - 1 mRNA增加了2.5倍和2.0倍。我们得出结论，在人vSMC中，葡萄糖和胰岛素均可影响纤溶平衡，从而降低纤溶潜力。这可能导致局部纤溶作用降低，进而可能加速NIDDM患者的动脉粥样硬化血栓形成过程。
