Center for Advanced Studies and Technology (CAST), Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University, Chieti, Italy.
Center for Advanced Studies and Technology (CAST), Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, "G.d'Annunzio" University, Chieti, Italy.
Adv Pharmacol. 2023;97:133-165. doi: 10.1016/bs.apha.2022.12.001. Epub 2023 May 11.
Cyclooxygenase (COX) isozymes, i.e., COX-1 and COX-2, are encoded by separate genes and are involved in the generation of the same products, prostaglandin (PG)G and PGH from arachidonic acid (AA) by the COX and peroxidase activities of the enzymes, respectively. PGH is then transformed into prostanoids in a tissue-dependent fashion due to the different expression of downstream synthases. Platelets present almost exclusively COX-1, which generates large amounts of thromboxane (TX)A, a proaggregatory and vasoconstrictor mediator. This prostanoid plays a central role in atherothrombosis, as shown by the benefit of the antiplatelet agent low-dose aspirin, a preferential inhibitor of platelet COX-1. Recent findings have shown the relevant role played by platelets and TXA in developing chronic inflammation associated with several diseases, including tissue fibrosis and cancer. COX-2 is induced in response to inflammatory and mitogenic stimuli to generate PGE and PGI (prostacyclin), in inflammatory cells. However, PGI is constitutively expressed in vascular cells in vivo and plays a crucial role in protecting the cardiovascular systems due to its antiplatelet and vasodilator effects. Here, platelets' role in regulating COX-2 expression in cells of the inflammatory microenvironment is described. Thus, the selective inhibition of platelet COX-1-dependent TXA by low-dose aspirin prevents COX-2 induction in stromal cells leading to antifibrotic and antitumor effects. The biosynthesis and functions of other prostanoids, such as PGD, and isoprostanes, are reported. In addition to aspirin, which inhibits platelet COX-1 activity, possible strategies to affect platelet functions by influencing platelet prostanoid receptors or synthases are discussed.
环氧化酶（COX）同工酶，即 COX-1 和 COX-2，分别由不同的基因编码，通过酶的 COX 和过氧化物酶活性分别将花生四烯酸（AA）转化为相同的产物前列腺素（PG）G 和 PGH。PGH 然后由于下游合成酶的不同表达，以组织依赖性的方式转化为前列腺素。血小板中几乎只存在 COX-1，它生成大量血栓素（TX）A，一种促聚集和血管收缩的介质。这种前列腺素在动脉粥样血栓形成中起着核心作用，如低剂量阿司匹林（一种血小板 COX-1 的优先抑制剂）的抗血小板作用所证明的那样。最近的发现表明，血小板和 TXA 在与几种疾病相关的慢性炎症的发展中发挥了相关作用，包括组织纤维化和癌症。COX-2 响应炎症和有丝分裂刺激物在炎症细胞中生成 PGE 和 PGI（前列环素）。然而，PGI 在体内的血管细胞中持续表达，由于其抗血小板和血管扩张作用，在保护心血管系统中起着至关重要的作用。这里描述了血小板在调节炎症微环境中细胞 COX-2 表达中的作用。因此，低剂量阿司匹林通过选择性抑制血小板 COX-1 依赖性 TXA 来预防基质细胞中 COX-2 的诱导，从而产生抗纤维化和抗肿瘤作用。报告了其他前列腺素，如 PGD 和异前列烷的生物合成和功能。除了抑制血小板 COX-1 活性的阿司匹林外，还讨论了通过影响血小板前列腺素受体或合成酶来影响血小板功能的可能策略。
