The chemistry of NO interactions with hemoglobin has been viewed as a means of mitigating NO vasoactivity (irreversible binding) and eliminating NO from the body (oxidation to nitrate). This presented a conundrum, as by scavenging endothelium-derived NO and thereby decreasing blood flow, Hb seemed to oppose its function in oxygen delivery to tissues. Work from this laboratory, however, has shown that under physiological conditions, Hb does not scavenge NO, but rather introduces new chemistry when pO2 is high that channels NO groups into products, such as S-nitrosothiol (SNO), that preserve its bioactivity. In particular, SNO-hemoglobin (SNO-Hb) has been shown to contribute to the classical systemic responses of hypoxic vasodilation and hyperoxic vasoconstriction. A remaining question is what role NO/Hb chemistry plays in regulation of pulmonary vascular responses. Recent studies on NO/red blood cell (RBC) interactions in the lung have shaped a new perspective on their role in hypoxic pulmonary vasoconstriction (HPV). It appears that RBCs sequester NO augmenting HPV. The challenge is now: to understand the chemistry of NO interaction with RBCs in the lung; to reconcile these data with synthesis of SNO-Hb taking place there; and ultimately to determine if SNO-Hb also regulates HPV. Wepropose that the allosteric environment - pH, pCO2, pO2 (different in pulmonary and systemic arterial blood--dictates whether Hb alternatively functions to store (Fe(III)NO-Hb), consume (Fe(III) - Hb + nitrate), or deliver (SNO-Hb) NO bioactivity. We suggest, moreover, that SNO-Hb opposes HPV. We address this proposal in 4 specific aims, which are: 1) To elucidate the effects of allosteric modulation by pH, pCO2, and pO2 on the interactions of NO with native Hb and RBCs; 2) To determine the ability of allosteric effectors to control the accessibility of SNO and Fe(II)NO complexes in Hb, as measured by functional responses in pulmonary arterial bioassays in vitro; 3) To establish the functional linkage between the allosteric transition, Hb/NO interactions, and pulmonary and systemic hemodynamics in an in vivo model; and 4) To determine SNO-Hb and Fe(II)NO-Hb levels in humans and to establish their relationship to pulmonary vascular tone.
| Schwab, David E; Stamler, Jonathan S; Singel, David J (2010) EPR spectroscopy of nitrite complexes of methemoglobin. Inorg Chem 49:6330-7 |
| Sheng, Huaxin; Yang, Wei; Fukuda, Shiro et al. (2009) Long-term neuroprotection from a potent redox-modulating metalloporphyrin in the rat. Free Radic Biol Med 47:917-23 |
| Zhu, Jun; Li, Sheng; Marshall, Zermeena M et al. (2008) A cystine-cysteine shuttle mediated by xCT facilitates cellular responses to S-nitrosoalbumin. Am J Physiol Cell Physiol 294:C1012-20 |
| Buckley, Barbara J; Li, Sheng; Whorton, A Richard (2008) Keap1 modification and nuclear accumulation in response to S-nitrosocysteine. Free Radic Biol Med 44:692-8 |
| Diesen, Diana L; Hess, Douglas T; Stamler, Jonathan S (2008) Hypoxic vasodilation by red blood cells: evidence for an s-nitrosothiol-based signal. Circ Res 103:545-53 |
| Granillo, Olivia M; Brahmajothi, Mulugu V; Li, Sheng et al. (2008) Pulmonary alveolar epithelial uptake of S-nitrosothiols is regulated by L-type amino acid transporter. Am J Physiol Lung Cell Mol Physiol 295:L38-43 |
| Gutsaeva, Diana R; Carraway, Martha Sue; Suliman, Hagir B et al. (2008) Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. J Neurosci 28:2015-24 |
| Reynolds, James D; Ahearn, Gregory S; Angelo, Michael et al. (2007) S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood. Proc Natl Acad Sci U S A 104:17058-62 |
| Nozik-Grayck, Eva; Whalen, Erin J; Stamler, Jonathan S et al. (2006) S-nitrosoglutathione inhibits alpha1-adrenergic receptor-mediated vasoconstriction and ligand binding in pulmonary artery. Am J Physiol Lung Cell Mol Physiol 290:L136-43 |
| Leinenweber, Stephen B; Sheng, Huaxin; Lynch, John R et al. (2006) Effects of a manganese (III) porphyrin catalytic antioxidant in a mouse closed head injury model. Eur J Pharmacol 531:126-32 |
Showing the most recent 10 out of 75 publications
