This proposal focuses on defining the role of Nox oxidase-derived hydrogen peroxide, and cytosolic NADPH and NADH redox systems in processes that control signaling mechanisms regulating vascular smooth muscle force responses to physiological changes in PO2.Studies in this application investigate the importance of our new evidence that cytosolic NADPH and possibly NADH levels control a baseline Nox oxidase-derived hydrogen peroxide-mediated relaxation of bovine pulmdnary arteries which is removed by hypoxia, resulting in contraction. On the other hand, bovine coronary arteries maintain a lower level of NADPH and the NADPH generating pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase. We hypothesize that differences in the function of the PPP in coronary arteries results in a hypoxia-elicited oxidation of cytosolic NADPH, which activates relaxation through a mechanism we have shown to be controlled by the PPP.Studies in Aim 1 will investigate how PO2 regulates the expression of vascular responses involving Nox-derived hydrogen peroxide.
Aim 2 focuses on understanding how PO2 regulates cytosolic NADH and NADPH redox-linked signaling mechanisms that contribute to the control of force generation. Studies in Aim 3 are to define the origins of differences in the control of Nox oxidase activity and cytosolic NAD(P)H redox that contribute to hypoxia-elicited contractile and relaxing responses observed in pulmonary and coronary arteries. Isolated endothelium-removed coronary and pulmonary conduit and resistance arteries will be studied with perturbations that alter Nox activity and expression, and cytosolic NADH and NADPH redox to define how signaling systems regulated by these processes may function in PO2-elicited responses. The control of cytosolic NAD(P)H redox and oxidant production by PO2 will be examined with a combination of metabolic measurements, tissue fluorescence and chemiluminescent techniques, and cellular fluorescence imaging approaches which are designed to characterize the ROS and redox aspects of the signaling mechanisms that are involved. Rat arteries will also be examined to identify similarities and differences in mechanisms of PO2-elicited responses controlled by Nox and cytosolic NAD(P)H redox. These studies should help define the origins of differences in physiological responses of pulmonary and coronary arteries to changes in O2 tension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066331-09
Application #
7755012
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
2000-09-30
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
9
Fiscal Year
2010
Total Cost
$302,952
Indirect Cost
Name
New York Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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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
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
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
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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