Alpha2-antiplasmin: potential therapeutic roles in fibrin survival and removal.
Alpha2-antiplasmin: potential therapeutic roles in fibrin survival and removal.
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DOI：
10.2174/1568016043356228
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发表时间：
2004-10-01
期刊：
影响因子：
--
通讯作者：
McKee, Patrick A
中科院分区：
文献类型：
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作者：
Lee, Kyung N;Jackson, Kenneth W;McKee, Patrick A
α2-抗纤溶酶(α2AP)是纤溶酶的主要抑制物，纤溶酶是一种消化纤维蛋白的蛋白酶，纤维蛋白是血液凝块的主要成分。人血浆中存在两种形式的α2AP：以蛋氨酸为氨基末端的464位残基蛋白(Met-alpha2AP)和以天冬酰胺为氨基末端的N端缩短的452位残基(Asn-alpha2AP)。人血浆α2AP浓度为1微米，由约30%的甲硫氨酸-α2AP和约70%的天冬氨酸-α2AP组成。主要形式(ASN-α2AP)在凝血过程中被激活的凝血因子XIII迅速与纤维蛋白交联，结果是纤维蛋白变得对纤溶更具抵抗力。很明显，α2AP在调节纤维蛋白的有效性和持久性方面很重要，因为它对纤溶酶消化和去除的敏感性有影响。因此，α2AP的生理作用表明，它可能是开发更有效的血栓性疾病治疗的有用靶点。对Alpha2AP的研究似乎正朝着两个主要方向发展：(1)努力使用不同形式的Alpha2AP来减少继发于溶栓治疗的出血，同时不减缓血栓溶解；(2)努力使用不同形式来降低Alpha2AP作为纤溶酶抑制物的活性，从而增强纤溶。实现这两个目标的方法主要包括操纵alpha2AP分子结构中的特定功能结构域，或抑制一种新描述的被称为抗纤溶酶裂解酶的新型血浆蛋白酶，该酶可产生更有利的alpha2AP形式，ASN-alpha2AP，用于与纤维蛋白交联。抗纤溶酶裂解酶在一级结构和催化性质上与成纤维细胞激活蛋白/seprase相似。这篇综述综述了最近的研究，这些研究有望调节α2AP的活性及其与某些蛋白质的相互作用，作为预防和治疗血栓性疾病的新的治疗策略。
Alpha2-antiplasmin (alpha2AP) is the primary inhibitor of plasmin, a proteinase that digests fibrin, the main component of blood clots. Two forms of alpha2AP circulate in human plasma: a 464-residue protein with methionine as the amino-terminus (Met-alpha2AP) and an N-terminally-shortened 452-residue form with asparagine as the amino-terminus (Asn-alpha2AP). Human plasma alpha2AP concentration is 1 micro M and consists of approximately 30% Met-alpha2AP and approximately 70% Asn-alpha2AP. The major form (Asn-alpha2AP) is rapidly crosslinked to fibrin during blood clotting by activated coagulation factor XIII and as a consequence, fibrin becomes more resistant to fibrinolysis. It is apparent that alpha2AP is important in modulating the effectiveness and persistence of fibrin with respect to its susceptibility to digestion and removal by plasmin. Hence, the physiologic role of alpha2AP suggests that it may be a useful target for developing more effective treatment of thrombotic diseases. Research on alpha2AP appears to be moving in two main directions: (1) efforts to use variant forms of alpha2AP to reduce bleeding secondary to thrombolytic therapy while not slowing thrombolysis; and (2) efforts to use variant forms to diminish the activity of alpha2AP as a plasmin inhibitor so that fibrinolysis becomes enhanced. Methods to accomplish these two goals mostly involve manipulation of defined functional domains within the molecular structure of alpha2AP, or inhibition of a newly described novel plasma proteinase, termed antiplasmin-cleaving enzyme, that generates the more favorable form of alpha2AP, Asn-alpha2AP, for crosslinking to fibrin. The antiplasmin-cleaving enzyme has similarity in primary structure and catalytic properties to fibroblast activation protein/seprase. This review summarizes recent studies that may hold promise for modulating alpha2AP activity and its interactions with certain proteins as new therapeutic strategies for preventing and treating thrombotic disorders.