The long-term goals of this project are to identify and elucidate the physiological and pathophysiological signaling mechanisms involved in the regulation of pulmonary vascular function mediated by modulation of cGMP generation by poorly understood processes that control the soluble form of guanylate cyclase (sGC). Our studies focus on integrating our understanding in isolated bovine pulmonary arteries of how heme metabolism and various redox-related processes interact with the metabolism of reactive oxygen species (ROS) and nitric oxide (NO) in the control of pulmonary arterial smooth muscle force through mechanisms involving the regulation of sGC.
Aim 1 investigates defining how the modulation of specific pathways regulating Nox oxidases by mediators promoting pulmonary hypertension (PH) control pulmonary arterial smooth muscle force through ROS mechanisms that regulate the activity of sGC. Studies in Aim 2 examine how cytosolic NADH, NADPH and glutathione redox regulate sGC through modulating oxidation of its thiol and heme sites, with an emphasis on identifying how these mechanisms of sGC regulation contribute to the actions of PH mediators and inhibit vascular responses involving nitric oxide (NO) and ROS.
Aim 3 studies examine how the control of heme biosynthesis by aminolevulinic acid (ALA) generating protoporphyrin IX, and heme metabolism by heme oxygenase (HO) regulate the activity of sGC and its control of pulmonary vascular force by cGMP. Endothelium-removed bovine pulmonary arteries are studied with a combination of physiological function, molecular signaling, organ culture, transfection and metabolic modulation approaches to investigate mechanisms controlling sGC and its influence on vascular force through cGMP. Arteries from mice deficient in Nox-2 and p47phox Nox oxidase subunits, glucose-6-phopshate dehydrogenase needed to maintain cytosolic NADPH, and HO-2 are used to support mechanistic studies by defining their role in regulating sGC. Pulmonary arteries from monocrotaline-induced PH rats are examined to identify alterations in the regulation of sGC by the Nox oxidase, ROS and redox systems investigated. The regulation of sGC by ALA-elicited protoporphyrin IX generation is examined in a manner that determines if it stimulates sGC in a manner that has potential for therapeutic development as a pulmonary vasodilator which is resistant to oxidant conditions that are likely to be inhibiting sGC in PH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031069-25
Application #
7809485
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Moore, Timothy M
Project Start
1984-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
25
Fiscal Year
2010
Total Cost
$278,250
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
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
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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