The long-term goal of this project is to improve our understanding of the NO-dependent O2 transport functions of hemoglobin (Hb). In the lung, NO binds to the thiol of Hb upon oxygenation (R conformation), and the (S)NO group is released in the periphery upon deoxygenation (T structure). Thus, allosterically-controlled NO release from Hb participates in the regulation of peripheral blood flow. However, very little is known of how NO affects the functional behavior of Hb, i.e., its O2 binding and allosteric properties, or what effect NO has on pulmonary vascular tone or regional ventilation-perfusion relationships (V/Q), all of which critically influence tissue oxygenation. The following hypotheses will be tested: 1) That nitrosylation can affect the cooperative properties of Hb in a meaningful way, either by increasing O2 affinity or by facilitating O2 release in the periphery (i.e., by reinforcing the R or T structures through binding thiols or hemes, respectively). 2) That the effects of S-nitrosohemoglobin (SNO-Hb) on pulmonary vascular tone and V/Q matching are dependent on the PO2. 3) That an improved understanding of the structure and the functional behavior of SNO-Hb and nitrosylHb can be used to make measurements of these species in human blood. Ultimately, these studies should lead to a better understanding of the function-regulating interactions between NO and protein, the respiratory functions of Hb, and the O2-dependent control of pulmonary vascular tone. Our results may also have implications in disease states such as sepsis, sickle cell anemia, and persistent pulmonary hypertension of the newborn, and in therapeutic settings such as the use of inhaled NO, where O2 delivery and Hb functions are altered.
| McMahon, Timothy J; Ahearn, Gregory S; Moya, Martin P et al. (2005) A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension. Proc Natl Acad Sci U S A 102:14801-6 |
| McMahon, Timothy J; Moon, Richard E; Luschinger, Ben P et al. (2002) Nitric oxide in the human respiratory cycle. Nat Med 8:711-7 |
| Nozik-Grayck, Eva; McMahon, Timothy J; Huang, Yuh-Chin T et al. (2002) Pulmonary vasoconstriction by serotonin is inhibited by S-nitrosoglutathione. Am J Physiol Lung Cell Mol Physiol 282:L1057-65 |
| McMahon, T J; Exton Stone, A; Bonaventura, J et al. (2000) Functional coupling of oxygen binding and vasoactivity in S-nitrosohemoglobin. J Biol Chem 275:16738-45 |
