Hemoglobin beta 93 Cysteine Is Not Required for Export of Nitric Oxide Bioactivity From the Red Blood Cell

Article

关键词: SOLUBLE GUANYLATE-CYCLASE;    S-NITROSOHEMOGLOBIN;    FLOW REGULATION;    SNO-HEMOGLOBIN;    MECHANISM;    OXIDATION;    IDENTIFICATION;    ERYTHROCYTES;    BETA-CYS93;    SYNTHASE;   

DOI  :  10.1161/CIRCULATIONAHA.118.039284

来源: SCIE

【 摘 要 】

Background: Nitrosation of a conserved cysteine residue at position 93 in the hemoglobin beta chain (beta 93C) to form S-nitroso (SNO) hemoglobin (Hb) is claimed to be essential for export of nitric oxide (NO) bioactivity by the red blood cell (RBC) to mediate hypoxic vasodilation and cardioprotection. Methods: To test this hypothesis, we used RBCs from mice in which the beta 93 cysteine had been replaced with alanine (beta 93A) in a number of ex vivo and in vivo models suitable for studying export of NO bioactivity. Results: In an ex vivo model of cardiac ischemia/reperfusion injury, perfusion of a mouse heart with control RBCs (beta 93C) pretreated with an arginase inhibitor to facilitate export of RBC NO bioactivity improved cardiac recovery after ischemia/reperfusion injury, and the response was similar with beta 93A RBCs. Next, when human platelets were coincubated with RBCs and then deoxygenated in the presence of nitrite, export of NO bioactivity was detected as inhibition of ADP-induced platelet activation. This effect was the same in beta 93C and beta 93A RBCs. Moreover, vascular reactivity was tested in rodent aortas in the presence of RBCs pretreated with S-nitrosocysteine or with hemolysates or purified Hb treated with authentic NO to form nitrosyl(FeII)-Hb, the proposed precursor of SNO-Hb. SNO-RBCs or NO-treated Hb induced vasorelaxation, with no differences between beta 93C and beta 93A RBCs. Finally, hypoxic microvascular vasodilation was studied in vivo with a murine dorsal skin-fold window model. Exposure to acute systemic hypoxia caused vasodilatation, and the response was similar in beta 93C and beta 93A mice. Conclusions: RBCs clearly have the fascinating ability to export NO bioactivity, but this occurs independently of SNO formation at the beta 93 cysteine of Hb.

【 授权许可】

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