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Determining eNOS Binding and Circulation Modulating Effects of an Alpha Globin Mimetic Peptide (HbαX)
Author(s) -
Keller TC Stevenson,
Butcher Joshua T,
Swope Nicole K,
Columbus Linda,
Isakson Brant E
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.833.7
Subject(s) - enos , vasodilation , nitric oxide synthase , hemoglobin , chemistry , nitric oxide , globin , angiotensin ii , medicine , endocrinology , pharmacology , biochemistry , biology , receptor
The ability of hemoglobin to scavenge the potent vasodilator nitric oxide (NO) in the blood has been well established as a mechanism of vascular tone homeostasis. In endothelial cells, the alpha chain of hemoglobin (hereafter, alpha globin) and endothelial NO synthase (eNOS) form a macromolecular complex, providing a sink for NO directly adjacent to the production source. We have developed an alpha globin mimetic peptide (named HbαX) that displaces endogenous alpha globin and increases bioavailable NO for vasodilation. Initially we performed structural analysis of HbαX via solution NMR in order to better understand the interaction of alpha globin and eNOS. Next we show that, in vivo, HbαX administration increases capillary oxygenation and blood flow in arterioles acutely and produces a sustained decrease in systolic blood pressure in normal and angiotensin II–induced hypertensive states. HbαX acts with high specificity and affinity to endothelial NO synthase, without toxicity to liver and kidney and no effect on p50 of O 2 binding in red blood cells. In human vasculature, HbαX blunts vasoconstrictive response to cumulative doses of phenylephrine, a potent constricting agent. By binding to endothelial NO synthase and displacing endogenous alpha globin, HbαX modulates important metrics of vascular function, increasing vasodilation and flow in the resistance vasculature. Support or Funding Information Funding: HL088554, HL120840.