Control of tissue oxygenation by S-nitrosohemoglobin in human subjects

Abstract

S-Nitrosohemoglobin (SNO-Hb) is unique among vasodilators in coupling blood flow to tissue oxygen requirements, thus fulfilling an essential function of the microcirculation. However, this essential physiology has not been tested clinically. Reactive hyperemia following limb ischemia/occlusion is a standard clinical test of microcirculatory function, which has been ascribed to endothelial nitric oxide (NO). However, endothelial NO does not control blood flow governing tissue oxygenation, presenting a major quandary. Here we show in mice and humans that reactive hyperemic responses (i.e., reoxygenation rates following brief ischemia/occlusion) are in fact dependent on SNO-Hb. First, mice deficient in SNO-Hb (i.e., carrying C93A mutant Hb refractory to S-nitrosylation) showed blunted muscle reoxygenation rates and persistent limb ischemia during reactive hyperemia testing. Second, in a diverse group of humans—including healthy subjects and patients with various microcirculatory disorders—strong correlations were found between limb reoxygenation rates following occlusion and both arterial SNO-Hb levels (n = 25; P = 0.042) and SNO-Hb/total HbNO ratios (n = 25; P = 0.009). Secondary analyses showed that patients with peripheral artery disease had significantly reduced SNO-Hb levels and blunted limb reoxygenation rates compared with healthy controls (n = 8 to 11/group; P < 0.05). Low SNO-Hb levels were also observed in sickle cell disease, where occlusive hyperemic testing was deemed contraindicated. Altogether, our findings provide both genetic and clinical support for the role of red blood cells in a standard test of microvascular function. Our results also suggest that SNO-Hb is a biomarker and mediator of blood flow governing tissue oxygenation. Thus, increases in SNO-Hb may improve tissue oxygenation in patients with microcirculatory disorders.

A natural heme deficiency exists in biology that allows nitric oxide to control heme protein functions by regulating cellular heme distribution

“…For example, by measuring forearm blood flow or skin conductance [ 66 ] in response to the different sGC agonists, one could investigate the impact of a high‐nitrate diet [ 63 ] or of breathing a medically approved level of NO‐supplemented air. [ 65 ] Possible correlations could be investigated between the sGC agonist response and the level of NO in exhaled air from the lungs, [ 67 ] the level of S‐nitrosated Hb or heme‐nitrosyl Hb present in the blood, [ 68 ] and/or the overall NO production as measured by nitrate levels in blood and urine samples (e.g., in highland versus lowland populations). [ 69 ] If results obtained with the sGC agonists proved interesting, perhaps the heme content of other heme proteins could also be assessed from a tissue or cell sample obtained in some minimally invasive way.…”

Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport

“…In patients with peripheral arterial disease, tissue reoxygenation was slowed and SNO-Hb values were depressed. Taken together these findings indicate a role for SNO-Hb in the metabolite-driven (and O 2 -sensitive) hyperemic response to reperfusion, a clinically relevant adaptive response involving hypoxic vasodilation and RBCs ( Reynolds et al, 2023 ).…”

Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo

“… 1 5 The vasoregulatory activities of RBC-derived SNOs are impaired under some circumstances, for example during conventional blood (RBC) banking. 3 4 After the transfusion of banked RBCs, these lesions may contribute to impaired O 2 uptake by the lung 5 and O 2 delivery to tissues, 36 and to organ dysfunction and other disappointing outcomes in the transfused recipient. 2 37 In order to test the in vivo significance and the LAT1 dependence of CSNO uptake by ECs, we performed RBC transfusions in LAT1 ECKD and control transgenic mice.…”