title: Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia.
abstract: 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.
authors: Institute for Transformative Molecular Medicine and Departments of Medicine and.
authors: Rongli
authors: R
authors: Zhang
authors: Institute for Transformative Molecular Medicine and Departments of Medicine and.
authors: Douglas T
authors: DT
authors: Hess
authors: Institute for Transformative Molecular Medicine and Departments of Medicine and.
authors: Zhaoxia
authors: Z
authors: Qian
authors: Institute for Transformative Molecular Medicine and Departments of Medicine and.
authors: Alfred
authors: A
authors: Hausladen
authors: Institute for Transformative Molecular Medicine and Departments of Medicine and.
authors: Fabio
authors: F
authors: Fonseca
authors: Institute for Transformative Molecular Medicine and Departments of Medicine and.
authors: Ruchi
authors: R
authors: Chaube
authors: Institute for Transformative Molecular Medicine and Anesthesiology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; and.
authors: James D
authors: JD
authors: Reynolds
authors: Institute for Transformative Molecular Medicine and Departments of Medicine and Harrington Discovery Institute, University Hospitals Case Medical Center, Cleveland, OH 44106 jonathan.stamler@case.edu.
authors: Jonathan S
authors: JS
authors: Stamler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002319:Cardiovascular System; D017931:DNA Primers / Q000235:genetics; D004452:Echocardiography; D006439:Hemodynamics / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics; D010100:Oxygen / Q000378:metabolism*; D026403:S-Nitrosothiols; D014664:Vasodilation / Q000502:physiology*; D055544:beta-Globins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D026403:S-Nitrosothiols; D055544:beta-Globins; D010100:Oxygen
keywords: S-nitrosohemoglobin; S-nitrosylation; hypoxic vasodilation; nitric oxide