Essential Role of Hemoglobin βCys93 in Cardiovascular Physiology - PubMed (original) (raw)

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Essential Role of Hemoglobin βCys93 in Cardiovascular Physiology

Richard T Premont et al. Physiology (Bethesda). 2020.

Abstract

The supply of oxygen to tissues is controlled by microcirculatory blood flow. One of the more surprising discoveries in cardiovascular physiology is the critical dependence of microcirculatory blood flow on a single conserved cysteine within the β-subunit (βCys93) of hemoglobin (Hb). βCys93 is the primary site of Hb _S_-nitrosylation [i.e., _S_-nitrosothiol (SNO) formation to produce _S_-nitrosohemoglobin (SNO-Hb)]. Notably, _S_-nitrosylation of βCys93 by NO is favored in the oxygenated conformation of Hb, and deoxygenated Hb releases SNO from βCys93. Since SNOs are vasodilatory, this mechanism provides a physiological basis for how tissue hypoxia increases microcirculatory blood flow (hypoxic autoregulation of blood flow). Mice expressing βCys93A mutant Hb (C93A) have been applied to understand the role of βCys93, and RBCs more generally, in cardiovascular physiology. Notably, C93A mice are unable to effect hypoxic autoregulation of blood flow and exhibit widespread tissue hypoxia. Moreover, reactive hyperemia (augmentation of blood flow following transient ischemia) is markedly impaired. C93A mice display multiple compensations to preserve RBC vasodilation and overcome tissue hypoxia, including shifting SNOs to other thiols on adult and fetal Hbs and elsewhere in RBCs, and growing new blood vessels. However, compensatory vasodilation in C93A mice is uncoupled from hypoxic control, both peripherally (e.g., predisposing to ischemic injury) and centrally (e.g., impairing hypoxic drive to breathe). Altogether, physiological studies utilizing C93A mice are confirming the allosterically controlled role of SNO-Hb in microvascular blood flow, uncovering essential roles for RBC-mediated vasodilation in cardiovascular physiology and revealing new roles for RBCs in cardiovascular disease.

Keywords: S-nitrosothiol; S-nitrosylation; hemoglobin; microcirculation; vasodilation.

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Figures

FIGURE 1.

FIGURE 1.

Hypoxic autoregulation of blood flow In the classic demonstration of hypoxic autoregulation of blood flow (45), blood flow through muscle increases linearly as the oxygen saturation of the Hb entering the muscle decreases, maintaining relatively constant oxygen delivery.

FIGURE 2.

FIGURE 2.

Allosteric linkage of Hb conformation to O2 and SNO release Left: due to cooperativity, Hb in the presence of air in the lung will bind fully to four oxygen molecules (oxygenated, R-state Hb). A fraction of oxygenated Hb will also bind and stabilize SNO at Hb βCys93. Right: on reaching hypoxic tissues, Hb will cooperatively give off all four oxygen molecules during transition to the deoxygenated T-state (improving tissue oxygenation). Liberation of oxygen will cause T-state Hb βCys93-SNO to liberate SNO, which can now transfer to other cellular thiols (R-S-H), leading to vasorelaxation (SNO-mediated vasodilation).

FIGURE 3.

FIGURE 3.

Cardiovascular physiology regulated by βCys93 Mice lacking βCys93 have altered physiological responses due to the inability to carry and deliver SNO from Hb βCys93. These include reduced basal tissue oxygenation and blood flow (1), RBC adaptation to loss of function (2), reduced hypoxic vasodilation (active hyperemia) (3), reduced reactive hyperemia (4), absent short-term potentiation of ventilation (5), reduced resilience to cardiac injury (ischemia- and pressure overload-induced) (6), and reduced fetal transition to free-living adulthood (7). Hypothesized effects also include altered ventilation-perfusion (V/Q) matching in the lung and reduced resilience to hypoxia-driven pulmonary hypertension (8).

FIGURE 4.

FIGURE 4.

_S_-nitrosothiol compensation by humanized βCys93Ala red blood cells Left: in normal RBCs and humanized Hb RBCs, SNO is carried on Hb primarily on βCys93, with minor contributions by the other Cys residues on Hb, αCys104, and βCys112. Additionally, other low molecular weight thiols and proteins, including fetal Hb γCys93, can carry SNO within RBCs (LMW-SNO; γCys93-SNO). Right: in C93A RBCs, the βCys93Ala residue (Ala93) is unable to carry SNO, but the other Hb cysteine residues show elevated SNO levels, and fetal Hb retains γCys93-SNO, which provides essential residual function (since Cys93 is invariant and βC93A mice show reduced survival). Furthermore, LMW-SNO levels are also increased. Although total RBC SNO level is essentially unchanged by C93A mutation, the distribution within RBCs and on Hb is greatly altered. Most importantly, these other Hb Cys residues carrying SNO and the LMW-SNO species do not show allosteric coupling of SNO release to hypoxia and Hb R-to-T-state transition, but instead will release SNO independent of oxygen level.

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