Centro Enrica Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Biochem Pharmacol. 2013 Feb 15;85(4):525-30. doi: 10.1016/j.bcp.2012.11.023. Epub 2012 Dec 5.
The administration of thrombolytic drugs is of proven benefit in a variety of clinical conditions requiring acute revascularization, including acute myocardial infarction (AMI), ischemic stroke, pulmonary embolism, and venous thrombosis. Generated plasmin can degrade non-target proteins, including apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoproteins (HDL). Aim of the present study was to compare the extent of apoA-I proteolytic degradation in AMI patients treated with two thrombolytic drugs, alteplase and the genetically engineered t-PA variant tenecteplase. ApoA-I degradation was evaluated in sera from 38 AMI patients treated with alteplase or tenecteplase. In vitro, apoA-I degradation was tested by incubating control sera or purified HDL with alteplase or tenecteplase at different concentrations (5-100 μg/ml). Treatment with alteplase and tenecteplase results in apoA-I proteolysis; the extent of apoA-I degradation was more pronounced in alteplase-treated patients than in tenecteplase-treated patients. In vitro, the extent of apoA-I proteolysis was higher in alteplase-treated sera than in tenecteplase-treated sera, in the whole drug concentration range. No direct effect of the two thrombolytic agents on apoA-I degradation was observed. In addition to apoA-I, apoA-IV was also degraded by the two thrombolytic agents and again proteolytic degradation was higher with alteplase than tenecteplase. In conclusion, this study indicates that both alteplase and tenecteplase cause plasmin-mediated proteolysis of apoA-I, with alteplase resulting in a greater apoA-I degradation than tenecteplase, potentially causing a transient impairment of HDL atheroprotective functions.
溶栓药物在多种需要急性再血管化的临床情况下具有明确的益处，包括急性心肌梗死（AMI）、缺血性脑卒中、肺栓塞和静脉血栓形成。生成的纤溶酶可以降解非靶蛋白，包括载脂蛋白 A-I（apoA-I），其是高密度脂蛋白（HDL）的主要蛋白质成分。本研究的目的是比较两种溶栓药物，阿替普酶和基因工程 t-PA 变体替奈普酶治疗 AMI 患者时 apoA-I 蛋白水解降解的程度。在接受阿替普酶或替奈普酶治疗的 38 例 AMI 患者的血清中评估 apoA-I 降解。在体外，通过在不同浓度（5-100μg/ml）下孵育对照血清或纯化的 HDL 与阿替普酶或替奈普酶来测试 apoA-I 降解。阿替普酶和替奈普酶的治疗导致 apoA-I 蛋白水解；阿替普酶治疗患者的 apoA-I 降解程度比替奈普酶治疗患者更明显。在体外，在整个药物浓度范围内，阿替普酶治疗的血清中 apoA-I 蛋白水解的程度高于替奈普酶治疗的血清。两种溶栓剂对 apoA-I 降解没有直接影响。除 apoA-I 外，两种溶栓剂还降解 apoA-IV，并且阿替普酶的蛋白水解降解程度高于替奈普酶。总之，本研究表明阿替普酶和替奈普酶均导致纤溶酶介导的 apoA-I 蛋白水解，阿替普酶导致 apoA-I 降解程度大于替奈普酶，可能导致 HDL 抗动脉粥样硬化功能暂时受损。
