School of Life Sciences, University of Nottingham, Nottingham, UK.
School of Life Sciences, University of Nottingham, Nottingham, UK.
Vascul Pharmacol. 2023 Oct;152:107199. doi: 10.1016/j.vph.2023.107199. Epub 2023 Jul 25.
Myeloperoxidase (MPO) and its principal reaction product hypochlorous acid (HOCl) are part of the innate immune response but are also associated with endothelial dysfunction, thought to involve a reduction in nitric oxide (NO) bioavailability. We aimed to investigate the effect of MPO and HOCl on vasorelaxation of coronary arteries and to assess directly the involvement of NO. In addition, we hypothesised that the slow release hydrogen sulfide (HS) donor GYY4137 would salvage coronary artery endothelial function in the presence of MPO and HOCl.
Contractility of porcine coronary artery segments was measured using isometric tension recording. Incubation with MPO (50 ng/ml) plus hydrogen peroxide (HO) (30 μM; substrate for MPO) impaired endothelium-dependent vasorelaxation to bradykinin in coronary arteries. HOCl (10-500 μM) also impaired endothelium-dependent relaxations. There was no effect of MPO plus HO, or HOCl, on endothelium-independent relaxations to 5'-N-ethylcarboxamidoadenosine and sodium nitroprusside. L-NAME (300 μM), a NO synthase inhibitor, attenuated bradykinin relaxations, leaving L-NAME-resistant relaxations to bradykinin mediated by endothelium-dependent hyperpolarization. In the presence of L-NAME, MPO plus HO largely failed to impair endothelium-dependent relaxations to bradykinin. Similarly, HOCl failed to inhibit endothelium-dependent relaxations to bradykinin in the presence of L-NAME. GYY4137 (1-100 μM) protected endothelium-dependent relaxations to bradykinin from dysfunction caused by MPO plus HO, and HOCl, with no effect alone on bradykinin relaxation responses. The specific MPO inhibitor aminobenzoic acid hydrazide (ABAH) (1 and 10 μM) also protected against MPO plus HO-induced endothelial dysfunction (at 10 μM ABAH), but was less potent than GYY4137.
MPO plus HO, and HOCl, impair coronary artery endothelium-dependent vasorelaxation via inhibition of NO. GYY4137 protects against endothelial dysfunction in arteries exposed to MPO plus HO, and HOCl. HS donors such as GYY4137 are possible therapeutic options to control excessive MPO activity in cardiovascular diseases.
髓过氧化物酶（MPO）及其主要反应产物次氯酸（HOCl）是先天免疫反应的一部分，但也与内皮功能障碍有关，被认为涉及一氧化氮（NO）生物利用度的降低。我们旨在研究 MPO 和 HOCl 对冠状动脉血管舒张的影响，并直接评估 NO 的参与。此外，我们假设缓慢释放的硫化氢（HS）供体 GYY4137 将在存在 MPO 和 HOCl 的情况下挽救冠状动脉内皮功能。
使用等长张力记录测量猪冠状动脉段的收缩性。孵育 MPO（50ng/ml）加过氧化氢（HO）（30μM；MPO 的底物）可损害冠状动脉对缓激肽的内皮依赖性血管舒张作用。HOCl（10-500μM）也损害了内皮依赖性舒张作用。MPO 加 HO 或 HOCl 对 5'-N-乙基羧基酰胺腺苷和硝普钠的内皮非依赖性舒张没有影响。一氧化氮合酶抑制剂 L-NAME（300μM）减弱了缓激肽的舒张作用，使缓激肽介导的内皮依赖性超极化引起的 L-NAME 抗性舒张。在 L-NAME 存在的情况下，MPO 加 HO 基本上不能损害缓激肽引起的内皮依赖性舒张作用。同样，HOCl 不能抑制 L-NAME 存在时缓激肽引起的内皮依赖性舒张作用。GYY4137（1-100μM）可保护缓激肽引起的内皮依赖性舒张作用不受 MPO 加 HO 和 HOCl 引起的功能障碍的影响，而单独对缓激肽舒张反应没有影响。特异性 MPO 抑制剂氨基苯甲酸肼（ABAH）（1 和 10μM）也可防止 MPO 加 HO 引起的内皮功能障碍（在 10μM ABAH 时），但不如 GYY4137 有效。
MPO 加 HO 和 HOCl 通过抑制 NO 来损害冠状动脉内皮依赖性血管舒张。GYY4137 可防止暴露于 MPO 加 HO 和 HOCl 的动脉内皮功能障碍。HS 供体如 GYY4137 可能是控制心血管疾病中过度 MPO 活性的治疗选择。
