Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia

Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia - Zhang et al. (2015)

Key Points

Bioactive nitric oxide (NO) is stored in hemoglobin and transported within the red blood cells
In areas of hypoxia, this bioactive NO is released to facilitate vasodilation and allow easier transport of O2 into tissues
NO carried by the red blood cells is essential for tissue oxygenation and blood flow regulation

The Breathing Diabetic Summary

This is a fascinating study of nitric oxide (NO). In short, this paper shows that bioactive NO is “stored” in hemoglobin (Hb) and transported within the red blood cells (RBC). In areas of tissue hypoxia, this bioactive NO is released, which causes vasodilation, increases blood flow, and ultimately increases oxygen uptake in the tissues. Thus, tissue oxygenation is not only dependent on the amount of oxygen stored in the RBCs, but also on local blood flow, which they show is controlled by NO that “rides” on the RBCs themselves.

The main “star” of this paper is βCys93, which is modified by NO to become S-nitrosothiol (SNO). SNO is important because it retains the bioactivity of NO as it travels on the RBCs. To examine the importance of this mechanism, they replaced βCys93 in two groups of mice while keeping it in the control group. Thus, they were able to directly assess the importance of the βCys93-NO mechanism on tissue oxygenation and other parameters.

The first remarkable, but kind of sad result was that the litter size of the mutated mice was significantly reduced because there was not enough fetal blood flow without the SNO mechanism. For our purposes, the most important result was that blood flow and tissue oxygenation were both significantly reduced in the mutated mice versus the controls. They explain that, in areas of tissue hypoxia, bioactive NO would typically be released to increase blood flow and get more oxygen to the tissues. However, the mutated mice lacked this mechanism.

Another remarkable result was that the mice without βCys93 had reduced blood flow to the heart, which can lead to heart attacks. This is especially important to diabetics since we suffer from higher rates of cardiac disease.

Overall, this paper rewrites our understanding of blood flow regulation and tissue oxygenation. They show that a critical, if not the most critical, component of this process is βCys93 being modified by NO to form SNO, which is then transported in the RBCs where the bioactive NO can later be released to increase blood flow in areas of tissue hypoxia. This is important for us because, as the authors point out, diabetics suffer from altered levels of SNO. The nasal cavity is a reservoir of NO, and thus breathing through your nose day and night (Principle 1) could help increase blood flow and tissue oxygenation by increasing SNO.

Abstract from Paper

Oxygen delivery by Hb is essential for vertebrate life. Three amino acids in Hb are strictly conserved in all mammals and birds, but only two of those, a His and a Phe that stabilize the heme moiety, are needed to carry O2. The third conserved residue is a Cys within the β-chain (βCys93) that has been assigned a role in S-nitrosothiol (SNO)-based hypoxic vasodilation by RBCs. Under this model, the delivery of SNO-based NO bioactivity by Hb redefines the respiratory cycle as a triune system (NO/O2/CO2). However, the physiological ramifications of RBC-mediated vasodilation are unknown, and the apparently essential nature of βCys93 remains unclear. Here we report that mice with a βCys93Ala mutation are deficient in hypoxic vasodilation that governs blood flow autoregulation, the classic physiological mechanism that controls tissue oxygenation but whose molecular basis has been a longstanding mystery. Peripheral blood flow and tissue oxygenation are decreased at baseline in mutant animals and decline excessively during hypoxia. In addition, βCys93Ala mutation results in myocardial ischemia under basal normoxic conditions and in acute cardiac decompensation and enhanced mortality during transient hypoxia. Fetal viability is diminished also. Thus, βCys93-derived SNO bioactivity is essential for tissue oxygenation by RBCs within the respiratory cycle that is required for both normal cardiovascular function and circulatory adaptation to hypoxia.

Journal Reference:

Rongli Zhang, Douglas T. Hess, Zhaoxia Qian, Alfred Hausladen, Fabio Fonseca, Ruchi Chaube, James D. Reynolds, and Jonathan S. Stamler, (2015) Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia, PNAS, www.pnas.org/cgi/doi/10.1073/pnas.1502285112.