GYY4137, a hydrogen sulfide donor, protects against endothelial dysfunction in porcine coronary arteries exposed to myeloperoxidase and hypochlorous acid

Abstract

Background and aims: 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 (H₂S) donor GYY4137 would salvage coronary artery endothelial function in the presence of MPO and HOCl.

Methods and results: Contractility of porcine coronary artery segments was measured using isometric tension recording. Incubation with MPO (50 ng/ml) plus hydrogen peroxide (H₂O₂) (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 H₂O₂, 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 H₂O₂ 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 H₂O₂, 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 H₂O₂-induced endothelial dysfunction (at 10 μM ABAH), but was less potent than GYY4137.

Conclusions: MPO plus H₂O₂, and HOCl, impair coronary artery endothelium-dependent vasorelaxation via inhibition of NO. GYY4137 protects against endothelial dysfunction in arteries exposed to MPO plus H₂O₂, and HOCl. H₂S donors such as GYY4137 are possible therapeutic options to control excessive MPO activity in cardiovascular diseases.

Keywords: Coronary artery; Endothelium; Hydrogen sulfide; Hypochlorous acid; Myeloperoxidase.