Adam Straub, PhD
Associate Professor, Department of Pharmacology and Chemical Biology
Director, Center for Microvascular Research
Mechanisms of hemoglobin a-regulated nitric oxide signaling in endothelial cells
Nitric oxide (NO) signaling regulates arterial vascular reactivity in the microcirculation to control peripheral vascular resistance and thus blood pressure. Recently, it was reported for the first time that hemoglobin a is expressed in arterial endothelial cells (ECs), where it is in complex with endothelial nitric oxide synthase (eNOS) (Straub et al., Nature 2012). It was demonstrated that endothelial hemoglobin a is enriched at the myoendothelial junction, the point where endothelial cells and smooth muscle cells make contact in resistance arteries and arterioles, where it regulates the effect of NO signaling on vascular reactivity. Mechanistically, hemoglobin a heme iron in the Fe3+ state permits active NO signaling, and this signaling is shut off when hemoglobin a is reduced to the Fe2+ state by endothelial cytochrome B5 reductase 3 (CytB5R3). These data reveal a novel paradigm by which the regulation of intracellular hemoglobin oxidation controls NOS signaling in non-erythroid cells. This paradigm may be relevant to a broad range of other somatic cells discovered to express hemoglobin (i.e. neurons, renal mesangial cells, macrophages, sympathetic nerves, hepatocytes, alveolar epithelial cells, and endometrial cells) and also known to express NOS isoforms. Our studies will be a direct outgrowth of this work, where we will focus on the molecular, cellular, and in vivo contribution of somatic hemoglobins and CytB5Rs as it pertains to vascular physiology and disease.
NAD regulation and the NAMPT pathway in vascular physiology and disease
Nicotinamide adenine dinucleotide (NAD) is a fundamentally important molecule critical for many redox reactions in biology. Interestingly, the regulation of NAD+ and NAD(H) is dependent on cell type, which are governed by multiple mechanisms. One mechanism that regulates NAD+ levels is NAMPT, also known as pre-B cell colony factor (PBEF) or visfatin. Existing both as an extracellular and intracellular protein, NAMPT is a rate-limiting enzyme in the NAD+ biosynthesis pathway and is vital for embryonic development since homozygous knockout mice are embryonic lethal (Revollo et al, 2007). The extracellular form of NAMPT stimulates both NAD+ and non-NAD+ signaling pathways in vascular cells, while intracellular NAD+ generated by NAMPT has been shown to regulate vascular cell longevity and protection against ischemia/reperfusion in the heart through a surtuin-1 dependent pathway (van der Veer et al 2007, Hsu et al, 2009). Although it has been established that intracellular NAMPT can regulate NAD+ levels, the downstream signaling pathways relying on this enzyme with regards to resistance arterial tone regulation remains elusive. Our goal is to better understand the role(s) of this enzyme in the microcirculation and in vascular biology in general.
Education and Training
PhD (Cardiovascular Toxicology), University of Pittsburgh Graduate School of Public Health, 2008
Postdoctoral Research Fellow (Vascular Biology), University of Virginia School of Medicine, 2013
View Selected Papers
Straub AC, AW Lohman, M Billaud, SR Johnstone, MY Lee, P Schoppee-Bortz, AK Best, ST Dwyer, L Columbus, B Gaston and BE Isakson. Endothelial cell expression of hemoglobin alpha regulates nitric oxide signaling. Nature 491:473-477, 2012.
Straub AC, M Billaud, SR Johnstone, AK Best, S Yemen, ST Dwyer, R Looft-Wilson, JJ Lysiak, B Gaston, LA Palmer and BE Isakson. Compartmentalized connexin 43 S-nitrosylation/denitrosylation regulates heterocellular communication in the vessel wall. Arterioscler Thromb Vasc Biol 31:399-407, 2011.
Billaud M, AW Lohman, AC Straub, R Looft-Wilson, SR Johnstone, CA Araj, AK Best, F Chekeni, K Ravichandran, S Penuela, D Laird and BE Isakson. Pannexin 1 regulates alpha 1-adrenergic receptor-mediated vasoconstriction. Circ Res 109:80-85, 2011.
Heberlein K, AC Straub, AK Best, RC Looft-Wilson and BE Isakson. Plasminogen activator inhibitor-1 can regulate myoendothelial junction formation. Circ Res 106:1092-1102, 2010.
Straub AC, KA Clark, MA Ross, AG Chandra, S Li, X Gao, PJ Pagano, DB Stolz and A Barchowsky. Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH-oxidase generated superoxide. J Clin Invest 118:3980-3989, 2008.