Steven Keller

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 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. Here 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 O2 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.

Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX).
Keller TC 4th, Butcher JT, Broseghini-Filho GB, Marziano C, DeLalio LJ, Rogers S, Ning B, Martin JN, Chechova S, Cabot M, Shu X, Best AK, Good ME, Simão Padilha A, Purdy M, Yeager M, Peirce SM, Hu S, Doctor A, Barrett E, Le TH, Columbus L, Isakson BE. Hypertension. (6):1494-1503 (2016).

Steven awarded an American Heart Association Predoctoral Fellowship

Steven was awarded an American Heart Association (AHA) Predoctoral Fellowship this May for his collaborative research between the Columbus and Isakson laboratories. AHA funds research related to cardiovascular function and disease and stroke, or to related clinical, basic science, bioengineering or biotechnology, and public health problems. Steven aims to investigate the molecular basis for the regulation of eNOS function by alpha globin and the physiological impact this interaction has on blood pressure regulation.

Shu X, Keller TC 4th, Begandt D, Butcher JT, Biwer L, Keller AS, Columbus L, Isakson BE.Endothelial nitric oxide synthase in the microcirculation
Cellular and Molecular Life Sciences 72:4561-75 (2015).

Isakson and Columbus receive Ivy Foundation Grant

The Ivy Foundation Biomedical Innovation Grants awarded Isakson and Columbus $80,000 in funding to develop novel anti-hypertensive therapeutics that target the hemoglobin alpha and eNOS interaction that they discovered.
Read more about other awards at UVA Today

Graduate Student

BS: Physics, Davidson College (2014)
Steven is a joint graduate student with Brant Isakson. His research focuses on the molecular interactions between alpha-globin and eNOS and the physiological consequences of this interaction.

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