Drinane M C, Sherman J A, Hall A E, Simons M, Mulligan-Kehoe M J
Department of Surgery, Vascular Section, Dartmouth Medical School, Lebanon, NH 03756, USA.
J Thromb Haemost. 2006 Jun;4(6):1288-95. doi: 10.1111/j.1538-7836.2006.01979.x.
While coronary artery disease (CAD) is associated with disturbances of the plasma fibrinolytic system, the nature of these disturbances is not fully defined. Fibrinolysis is regulated by plasmin, whose production is mediated by plasminogen activator conversion of plasminogen (Plg) to plasmin. The cascade is modulated by feedback loops that include Plg activator inhibitor 1 (PAI-1). Molecular interactions with Plg kringle domains play an important role in regulating plasmin production and its modulation of fibrinolysis. We hypothesized that interactions of tissue plasminogen activator (tPA) with Plg kringle domains regulates plasmin levels in patients with stable CAD.
Plasma was collected from patients (n = 33) with an angiographically significant CAD and controls (n = 18) with angiographically established normal or minimally diseased arteries. Plasmin activity, tPA activity, and plasma levels of Plg, PAI-1, uPA, and tPA were determined.
CAD patients had 1.7-fold greater plasmin activity (P = 0.02) that correlated with 1.5-fold higher tPA activity when compared to controls. Epitope mapping of Plg domains showed Plg differences in epitope exposure between the two groups. Plasma from CAD patients had 50% less (P < 0.001) detectable kringle 4 and 48% less (P = 0.007) detectable kringles 1-3.
Based on detectable differences in Plg, we conclude that in patients with stable CAD, Plg complexed with tPA exists in a conformation that enables increased tPA activity and Plg conversion to plasmin.
虽然冠状动脉疾病（CAD）与血浆纤维蛋白溶解系统紊乱有关，但这些紊乱的性质尚未完全明确。纤维蛋白溶解由纤溶酶调节，纤溶酶的产生是通过纤溶酶原激活剂将纤溶酶原（Plg）转化为纤溶酶介导的。该级联反应由包括纤溶酶原激活剂抑制剂1（PAI - 1）在内的反馈环调节。与Plg kringle结构域的分子相互作用在调节纤溶酶产生及其对纤维蛋白溶解的调节中起重要作用。我们假设组织纤溶酶原激活剂（tPA）与Plg kringle结构域的相互作用调节稳定型CAD患者的纤溶酶水平。
从血管造影显示有明显CAD的患者（n = 33）和血管造影显示动脉正常或病变轻微的对照组（n = 18）中采集血浆。测定纤溶酶活性、tPA活性以及Plg、PAI - 1、尿激酶型纤溶酶原激活剂（uPA）和tPA的血浆水平。
与对照组相比CAD患者的纤溶酶活性高1.7倍（P = 0.02），且与tPA活性高1.5倍相关。Plg结构域的表位作图显示两组之间Plg表位暴露存在差异。CAD患者血浆中可检测到的kringle 4减少50%（P < 0.001），可检测到的kringles 1 - 3减少48%（P = 0.007）。
基于Plg中可检测到的差异，我们得出结论，在稳定型CAD患者中，与tPA复合的Plg以一种能增加tPA活性和使Plg转化为纤溶酶的构象存在。
