Targeting PAR4 to Reduce Atherosclerosis.
Targeting PAR4 to Reduce Atherosclerosis.
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以 PAR4 为靶点，减少动脉粥样硬化。
DOI：
10.1161/atvbaha.123.320046
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Barrett,TessaJ
中科院分区：
文献类型：
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作者：
Barrett,TessaJ
血小板是血栓形成的关键，异常的血小板聚集是动脉缺血事件发生的基础。因此，抑制血小板活性的药物是预防心血管血栓事件（包括心肌梗死和卒中）的主要药物治疗。目前临床批准的药物用于抑制血栓形成，靶向5种血小板蛋白之一：细胞表面受体、整合素αIIbβ3、P2 Y12或PAR（蛋白酶激活受体）-1，以及细胞内信号酶考克斯（环氧合酶）-1和PDE（磷酸二酯酶;图）。此外，临床使用的凝血酶抑制剂（如达比加群、肝素、华法林）可抑制凝血酶介导的血小板活化。1，2尽管它们在抑制血栓形成方面有效，但所有目前批准的抗血小板剂都具有限制其临床疗效和实用性的缺点。例如，长期预防心血管疾病的主要药物阿司匹林和P2 Y12受体拮抗剂预防的复发性血栓形成事件不到20%，并且在一般人群中，由于出血风险增加，不推荐用于一级预防。3，4同样，PAR 1拮抗剂vorapaxar与阿司匹林和P2 Y12受体拮抗剂联合给药时，在几个患者组中引起高出血风险，5，6和αIIbβ3拮抗剂需要静脉给药，并显著增加获得性出血的可能性，排除了长期使用。目前抗血小板治疗的局限性促使人们不断努力发现新的血小板活化途径，并确定那些可以在治疗上靶向减少血栓形成的结果，同时避免不良副作用，包括增加出血风险。
Platelets are key to thrombosis, with aberrant platelet aggregation underlying the development of arterial ischemic events. Consequently, drugs that inhibit platelet activity are the primary pharmacotherapy for preventing cardiovascular thrombotic events, including myocardial infarction and stroke. Current clinically approved drugs used prophylactically to curtail thrombosis, target one of 5 platelet proteins: the cell surface receptors, integrin αIIbβ3, P2Y12, or PAR (protease-activated receptor)-1, and the intracellular signaling enzymes COX (cyclooxygenase)-1 and PDE (phosphodiesterase; Figure). In addition, clinically used thrombin inhibitors (eg, dabigatran, heparin, warfarin) suppress thrombin-mediated platelet activation. 1, 2 Despite their effectiveness in suppressing thrombosis, all currently approved antiplatelet agents have shortcomings restricting their clinical efficacy and utility. For example, the leading drugs for long-term cardiovascular disease prevention, aspirin and P2Y12 receptor antagonists, prevent fewer than 20% of recurrent thrombotic events and, in the general population, are not recommended for primary prevention due to increased bleeding risk. 3, 4 Similarly, the PAR1 antagonist vorapaxar causes high bleeding risk in several patient groups when administered in combination with aspirin and P2Y12 receptor antagonists, 5, 6 and αIIbβ3 antagonists require intravenous administration and significantly increase acquired bleeding potential, precluding their long-term use. 7, 8 The limitations of current antiplatelet therapies have driven ongoing efforts to uncover novel platelet activation pathways and identify those that can be therapeutically targeted to reduce thrombotic outcomes while circumventing undesirable side effects, including increased bleeding risk.