INDUCTION OF PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 (PAI-1) BY PROINSULIN AND INSULIN IN-VIVO
INDUCTION OF PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 (PAI-1) BY PROINSULIN AND INSULIN IN-VIVO
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DOI：
10.1161/01.cir.91.3.764
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发表时间：
1995-02-01
期刊：
影响因子：
37.8
通讯作者：
SOBEL, BE
中科院分区：
文献类型：
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作者：
NORDT, TK;SAWA, H;SOBEL, BE
空腹高胰岛素血症（反映为免疫反应性“胰岛素”升高）是非胰岛素依赖型糖尿病（NIDDM）患者的典型症状，通常与肥胖和高血压相关。检测到的浓度升高不仅表明胰岛素，而且表明其免疫交叉反应前体，包括胰岛素原。空腹高胰岛素血症似乎与血液中纤维蛋白溶解活性降低有关，这是由纤溶酶原激活物抑制剂1型（PAI-1）活性增加引起的，PAI-1是冠状动脉疾病的潜在独立危险因素。在先前的临床研究中给予胰岛素原的患者表现出心血管事件发生率增加。因此，“胰岛素原- pai -1轴”可能导致冠状动脉血栓形成。为了确定这种轴的可能存在，本研究旨在确定胰岛素及其前体或两者是否会增加兔体内PAI-1的浓度。方法和结果将等摩尔胰岛素原（n=10）、胰岛素（n=11）、c肽（n=4）或单独的载体（n=10）静脉注射至血糖正常、意识清醒的家兔1小时以上。血浆PAI-1活性在胰岛素原组增加3.8倍（P=.002），在胰岛素组增加3.6倍（P=.002）。相比之下，给予c肽或载体后未出现增加。反向纤维蛋白自显影显示PAI-1活性增加可归因于PAI-1蛋白。从组织mRNA的变化判断，胰岛素原和胰岛素在3小时内使PAI-1基因在主动脉中的表达分别增加2.1倍和2.1倍（P= 0.025），在肝脏中的表达分别增加1.9倍和2.4倍（P= 0.015和P= 0.001），并在24小时内恢复到基线值（各n=4个实验）。这些结果扩展了我们之前在体外研究中观察到的结果，表明血浆中胰岛素原和胰岛素浓度升高引起的高胰岛素血症增加了血浆PAI-1活性，可能加速了NIDDM患者动脉粥样硬化和冠状动脉溶栓功能的损害。
Background Fasting hyperinsulinemia (reflected by elevations in immunoreactive ''insulin'') is typical of patients with non-insulin-dependent diabetes mellitus (NIDDM) and is often associated with obesity and hypertension. The elevated concentrations detected are indicative not only of insulin but also of its immunologically cross-reactive precursors, including proinsulin. Fasting hyperinsulinemia appears to be associated with decreased fibrinolytic activity in blood, which results from increased activity of plasminogen activator inhibitor type-1 (PAI-1), a potential independent risk factor for coronary artery disease. Patients who were given proinsulin in a previous clinical study by others exhibited an increased incidence of cardiovascular events. Thus, a ''proinsulin-PAI-1 axis'' may predispose to coronary thrombosis. To define the possible presence of such an axis, this study was designed to determine whether insulin, its precursors, or both increase the concentrations of PAI-1 in rabbits in vivo.Methods and Results Equimolar proinsulin (n=10), insulin (n=11), C-peptide (n=4), or vehicle alone (n=10) was administered intravenously over 1 hour to euglycemic, conscious rabbits. Plasma PAI-1 activity increased 3.8-fold with proinsulin (P=.002) and 3.6-fold with insulin (P=.002). By contrast, no increase occurred after C-peptide or vehicle was administered. The increased PAI-1 activity was shown to be attributable to PAI-1 protein by reverse fibrin autography. As judged from changes in mRNA in tissues, proinsulin and insulin increased PAI-1 gene expression within 3 hours by 2.1- and 2.1-fold, respectively, in aorta (P=.025 each) and by 1.9- and 2.4-fold in liver (P=.015 and P=.001), with return of values to baseline within 24 hours (n=4 experiments in each case).Conclusions These results extend our previous observations from studies in vitro and suggest that hyperinsulinemia attributable to augmented concentrations of proinsulin and insulin in plasma increase plasma PAI-1 activity and may contribute to acceleration of atherosclerosis and impairment of coronary thrombolysis in patients with NIDDM.