Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: implications for vascular disease in hyperinsulinemic states.

Accelerated atherosclerosis accompanying diabetes mellitus, obesity, and some types of hypertension has been associated with hyperinsulinemia, augmented plasma plasminogen activator inhibitor type 1 (PAI-1), or both. We hypothesized that insulin and insulin-like growth factor type I (IGF-I) can influence synthesis of PAI-1, thereby potentially attenuating fibrinolysis. In HepG2 cells used as a model system, concentrations of insulin and IGF-I consistent with those seen in plasma independently stimulated PAI-1 synthesis. Accumulation of PAI-1 protein in conditioned medium over 24 hr was stimulated more with insulin alone than with the combination. Synergistic increases were evident, however, in the accumulation of PAI-1 protein over 48 hr with a concomitant increase in PAI-1 mRNA. A 10- to 20-fold increase in IGF binding protein I mRNA was seen 16-48 hr after exposure of the HepG2 cells to insulin and IGF-I, an increase abolished by cycloheximide. The results obtained are consistent with the hypothesis that hyperinsulinemia coupled with physiologic concentrations of IGF-I may attenuate fibrinolytic activity in vivo, thereby contributing to accelerated atherosclerosis. IMAGES:

伴随糖尿病、肥胖及部分亚型高血压的加速性动脉粥样硬化，已与高胰岛素血症、血浆纤溶酶原激活物抑制剂1型（PAI-1）水平升高，或二者同时存在显著关联。我们提出假说：胰岛素与胰岛素样生长因子I型（IGF-I）可调控PAI-1的合成，进而潜在削弱纤维蛋白溶解活性。在用作体外模型的HepG2细胞中，与血浆中生理浓度相当的胰岛素与IGF-I可独立刺激PAI-1的合成。24小时培养周期内，条件培养基中PAI-1蛋白的积累量在单独使用胰岛素时，高于二者联合使用的情况。然而，在48小时培养周期中，PAI-1蛋白的积累量与PAI-1 mRNA水平同步升高，二者呈现显著的协同增加效应。在HepG2细胞经胰岛素与IGF-I处理后的16至48小时内，胰岛素样生长因子结合蛋白I的mRNA水平升高10至20倍；该升高效应可被环己酰亚胺（cycloheximide）阻断。本研究所得结果与下述假说一致：高胰岛素血症联合生理浓度的IGF-I可在体内削弱纤维蛋白溶解活性，进而加速动脉粥样硬化的进展。图像：