The central hypothesis of this project is that extracellular SOD (ecSOD) activity has potentially beneficial important roles in controlling the expression of pulmonary hypertension resulting from exposure to chronic hypoxia through the generation of hydrogen peroxide and its stimulation of cGMP protein kinase (PKG). It is also hypothesized that increased expression of ecSOD is a process that contributes to the protective effects of heme oxygenase-1 (HO-1) elevation in pulmonary hypertension. While there is substantial evidence for HO-1 and ecSOD being beneficial in attenuating the development of pulmonary hypertension in several animal models, previous studies do not appear to have considered the mechanisms investigated in this application. Our recent studies document that peroxide can promote activation of PKG by a thiol oxidation-mediated PKG subunit dimerization mechanism which participates in relaxation of pulmonary arteries to extracellular hydrogen peroxide and responses to acute hypoxia. Preliminary data provide evidence that chronic hypoxia in vivo promotes both a dimerization activation of PKG and a suppression of force generation in isolated mouse pulmonary arteries by a process that is reversible by catalase. The studies proposed focus on using mice deficient in ecSOD or HO-1, a PKG knockin mouse that is modified to prevent thiol oxidation-activation of PKG by peroxide together with beneficial pulmonary hypertension therapies that increase ecSOD or HO-1 expression and promote PKG dimerization to investigate their roles in controlling the adaptation of pulmonary vascular function caused by exposure of mice to chronic hypoxia. Studies in Aim 1 define the influence of changes in ecSOD expression on processes contributing to the control of vascular function and remodeling involved in the development and reversal of hypoxia-induced pulmonary hypertension by utilizing mice either overexpressing or deficient in ecSOD.
Aim 2 focuses on defining how ecSOD expression functions through either increased peroxide regulation of PKG and/or through increased superoxide scavenging to increase nitric oxide (NO) utilizing PKG knockin mice which have a modification preventing PKG dimerization and mice deficient in endothelial nitric oxide synthase (eNOS). The focus of studies in Aim 3 is defining the influence of changes in ecSOD expression on the protective effects of HO-1 utilizing mice deficient in HO-1 or ecSOD and therapies to induce HO-1 and ecSOD. Studies will include ECHO-Doppler flow analysis of cardiopulmonary function, mechanistic functional studies in isolated pulmonary arteries, signaling studies related to PKG and processes influencing the redox regulation src kinase-mediated STAT-3 phosphorylation promoting expression of miR-204, a master gene regulatory system controlling the development and reversal of smooth muscle remodeling in pulmonary hypertension. These studies should provide definitive new mechanistic information on how the effects of chronic hypoxia promote the development of pulmonary hypertension, which could be beneficial in treating the progression of diseases such as COPD and sleep apnea.
This study examines how blood vessels are regulated when humans and animals are exposed to low oxygen levels. These conditions are associated with the development of pulmonary hypertension and right heart failure. These studies could help define the benefits of developing therapeutic approaches for the treatment of pulmonary hypertension and impaired delivery of oxygen to tissues based on increasing the function of a protective system that is being studied.
|Alruwaili, Norah; Kandhi, Sharath; Sun, Dong et al. (2018) Metabolism and Redox in Pulmonary Vascular Physiology and Pathophysiology. Antioxid Redox Signal :|
|Zhang, Bin; Alruwaili, Norah; Kandhi, Sharath et al. (2018) Inhibition of ferrochelatase impairs vascular eNOS/NO and sGC/cGMP signaling. PLoS One 13:e0200307|
|Gupte, Sachin A; Wolin, Michael S (2017) Mitochondrial Calcium Transport: A Potentially Prominent, Therapeutically Targetable Contributor to Pulmonary Arterial Hypertension Progression. Am J Respir Crit Care Med 195:420-421|
|Kandhi, Sharath; Zhang, Bin; Froogh, Ghezal et al. (2017) EETs promote hypoxic pulmonary vasoconstriction via constrictor prostanoids. Am J Physiol Lung Cell Mol Physiol 313:L350-L359|
|Patel, Dhara; Lakhkar, Anand; Wolin, Michael S (2017) Redox Mechanisms Influencing cGMP Signaling in Pulmonary Vascular Physiology and Pathophysiology. Adv Exp Med Biol 967:227-240|
|Lakhkar, Anand; Dhagia, Vidhi; Joshi, Sachindra Raj et al. (2016) 20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition. Am J Physiol Heart Circ Physiol 310:H1107-17|
|Patel, Dhara; Alhawaj, Raed; Kelly, Melissa R et al. (2016) Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II. Am J Physiol Heart Circ Physiol 310:H1439-47|
|Wolin, Michael S; Patel, Dhara; Alhawaj, Raed et al. (2016) Iron Metabolism and Vascular Remodeling: Novel Insights Provided by Transferrin-1 Receptor Depletion in Mice With Pulmonary Hypertension. Am J Hypertens 29:676-8|
|Kizub, Igor V; Lakhkar, Anand; Dhagia, Vidhi et al. (2016) Involvement of gap junctions between smooth muscle cells in sustained hypoxic pulmonary vasoconstriction development: a potential role for 15-HETE and 20-HETE. Am J Physiol Lung Cell Mol Physiol 310:L772-83|
|Kandhi, Sharath; Froogh, Ghezal; Qin, Jun et al. (2016) EETs Elicit Direct Increases in Pulmonary Arterial Pressure in Mice. Am J Hypertens 29:598-604|
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