The long-term goals of this project are to identify and elucidate the signal transduction mechanisms involved in the control of pulmonary vascular tone mediated by modulation of the production of the intracellular mediator of relaxation, cGMP, via regulation the soluble form of an integrated understanding of how various redox-related processes interact with the metabolism of reactive oxygen species and nitric oxide (NO) in the control of pulmonary vascular tone through mechanisms involving the regulation of sGC. The principal investigator proposes to systematically evaluate interactions that regulate sGC activity and its role in the control of pulmonary arterial smooth muscle force involving: (1) the potential role of endogenous vascular smooth muscle redox systems including cytosolic NAD and NADP, glutathione, microsomal and mitochondrial electron transport, with a focus on determining if H2O2, O2.- and the redox status of the heme on sGC are the central mechanisms through which these processes control the activity of sGC and vascular tone, (2) the relationships between these redox systems and the NO/O2.- interaction, with a focus on determining if thiol nitrosation is an important signaling process, and (3) to evaluate how interactions between the cellular redox systems examined, reactive O2 species and NO-derived species contribute to tone responses elicited by changes in PO2, with a focus on determining if the modulation of sGC activity is the primary signal transduction mechanism mediating responses that are observed. Much of the work in this proposal will also focus on developing an understanding of function and importance of NADH-cytochrome b558 O2.- producing electron transport chain, which the investigators have discovered during their recent work on this project in calf pulmonary arterial smooth muscle. This O2.- producing system seems to both be a major source of endogenous reactive O2 species and functions as a PO2 sensor that regulates sGC activity. The current proposal will employ isolated calf pulmonary arteries for tone studies with mechanistic probes, and measurements of endogenous reactive O2 species and cGMP production, and arterial smooth muscle subcellular fractions to identify the redox systems which generate activators and inhibitors of sGC. The processes examined in this proposal may contribute to further understanding aspects of oxygen-elicited regulation of the pulmonary circulation during normal physiology and when this circulation is exposed to pulmonary vascular pathophysiology associated with the formation of reactive oxygen and NO-derived species (e.g. acute lung injury/ARDS, ischemia reperfusion, hypertension, etc.).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL031069-14
Application #
2609221
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1984-04-01
Project End
2000-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
14
Fiscal Year
1998
Total Cost
Indirect Cost
Name
New York Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Neo, Boon Hwa; Patel, Dhara; Kandhi, Sharath et al. (2013) Roles for cytosolic NADPH redox in regulating pulmonary artery relaxation by thiol oxidation-elicited subunit dimerization of protein kinase G1?. Am J Physiol Heart Circ Physiol 305:H330-43
Chettimada, Sukrutha; Rawat, Dhwajbahadur K; Dey, Nupur et al. (2012) Glc-6-PD and PKG contribute to hypoxia-induced decrease in smooth muscle cell contractile phenotype proteins in pulmonary artery. Am J Physiol Lung Cell Mol Physiol 303:L64-74
Wolin, Michael S (2012) Novel role for the regulation of mitochondrial fission by hypoxia inducible factor-1? in the control of smooth muscle remodeling and progression of pulmonary hypertension. Circ Res 110:1395-7
Gupte, Sachin A; Wolin, Michael S (2012) Relationships between vascular oxygen sensing mechanisms and hypertensive disease processes. Hypertension 60:269-75
Neo, Boon Hwa; Kandhi, Sharath; Wolin, Michael S (2011) Roles for redox mechanisms controlling protein kinase G in pulmonary and coronary artery responses to hypoxia. Am J Physiol Heart Circ Physiol 301:H2295-304
Wolin, Michael S (2011) Plasma glutathione peroxidase activity is potentially a key regulator of vascular disease-associated thrombosis. Circulation 123:1923-4
Gupte, Rakhee S; Rawat, Dhawjbahadur K; Chettimada, Sukrutha et al. (2010) Activation of glucose-6-phosphate dehydrogenase promotes acute hypoxic pulmonary artery contraction. J Biol Chem 285:19561-71
Wolin, Michael S; Gupte, Sachin A; Neo, Boon Hwa et al. (2010) Oxidant-redox regulation of pulmonary vascular responses to hypoxia and nitric oxide-cGMP signaling. Cardiol Rev 18:89-93
Prieto, Dolores; Kaminski, Pawel M; Bagi, Zsolt et al. (2010) Hypoxic relaxation of penile arteries: involvement of endothelial nitric oxide and modulation by reactive oxygen species. Am J Physiol Heart Circ Physiol 299:H915-24
Neo, Boon Hwa; Kandhi, Sharath; Ahmad, Mansoor et al. (2010) Redox regulation of guanylate cyclase and protein kinase G in vascular responses to hypoxia. Respir Physiol Neurobiol 174:259-64

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