To provide a better understanding of the role of the regulation of the cytosolic form of guanylate cyclase in the control of pulmonary vascular tone is the long range objective of this proposal. The specific focus of the studies described in this application is to characterize and determine potential physiological mechanisms of pulmonary vascular regulation that involve modulation of the cytosolic form of guanylate cyclase, an enzyme which generates an intra-cellular mediator of vaso- relaxation, cyclic GMP. Our studies will attempt to elucidate the details of cyclic GMP associated mechanisms or modulation of smooth muscle tone and cytosolic guanylate cyclase regulation by hydrogen peroxide, the endothelium, changes in oxygen tension and exposure to light. A major aspect of the proposed studies will be directed toward the determination of the physiological significance of a new mechanism of activation of cytosolic guanylate cyclase by catalase mediated metabolism of peroxide that we have recently discovered. These problems will be investigated in isolated pulmonary vascular rings and with unpurified vascular and purified guanylate cyclase all obtained from bovine lungs. Measurements of changes in contractility, tissue cyclic GMP levels and guanylate cyclase activity in the presence of various agonists, antagonists and generators or scavengers of potential mediators will be employed to investigate and reconstruct the mechanisms of control of vascular tone and guanylate cyclase, and to characterize the mediators involved. Results of these studies will enable us to better understand some important physiological mechanisms of control of pulmonary vascular tone and provide the bsis for studies designed to determine their role in the pathogenesis of a variety of pulmonary vascular disorders related to pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031069-07
Application #
3342086
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1984-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
New York Medical College
Department
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Alhawaj, Raed; Patel, Dhara; Kelly, Melissa R et al. (2015) Heme biosynthesis modulation via ?-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308:L719-28
Patel, Dhara; Alhawaj, Raed; Wolin, Michael S (2014) Exposure of mice to chronic hypoxia attenuates pulmonary arterial contractile responses to acute hypoxia by increases in extracellular hydrogen peroxide. Am J Physiol Regul Integr Comp Physiol 307:R426-33
Patel, Dhara; Kandhi, Sharath; Kelly, Melissa et al. (2014) Dehydroepiandrosterone promotes pulmonary artery relaxation by NADPH oxidation-elicited subunit dimerization of protein kinase G 1?. Am J Physiol Lung Cell Mol Physiol 306:L383-91
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
Suematsu, Nobuhiro; Ojaimi, Caroline; Recchia, Fabio A et al. (2010) Potential mechanisms of low-sodium diet-induced cardiac disease: superoxide-NO in the heart. Circ Res 106:593-600

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