This Program Project Grant application describes studies we plan to perform as a continuation of our previous projects concerned with the regulation of cardiovascular function, primarily by endothelium-derived mediators, nitric oxide and reactive oxygen species. The present application builds on our previously obtained data to further establish the role of these agents in the control of vascular and cardiac function. Our overall hypothesis that we aim to test is that oxygen radical species, derived through activation of Nox oxidases in the vessel wall, by causing a reduction in nitric oxide bioavailability, hasten the development of vascular dysfunction leading to disease. In the first Project, Dr. Wolin will characterize how Nox-linked signaling mechanisms affect vascular function and how these mechanisms are altered in pathophysiologic conditions. In the second Project, Dr. Hintze will examine in mice, rats and dogs the role of NADPH oxidase in the increased oxidant production secondary to sodium restriction, a state associated with increased angiotensin production. He will also determine in the dog heart the effects of sodium restriction on NO dependent regulation of the coronary circulation as well as the fate of substrates and the alteration in the expression of metabolic enzymes. In the third Project, Dr. Kaley plans to study the effects of aging on vascular function in type 2 diabetic (db/db) and eNOS-KO mice, two different models of metabolic syndrome, each of which is characterized by increased oxidant stress and a reduction in nitric oxide bioavailability. The projects will be supported by three cores;one led by Dr. Edwards, providing genotyping of and physiologic measurements in mice, one led by Dr. Ungvari who will provide expertise in imaging ROS in vessels and tissues by state of the art methods and one led by Dr.
Oj aimi, who will interpret data obtained by gene array techniques. We believe that our research will provide conceptual advances that will likely lead to a better understanding of the development of vascular dysfunction in disease states as well as to novel therapeutic options.
|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|
|Huang, An; Pinto, John T; Froogh, Ghezal et al. (2015) Role of homocysteinylation of ACE in endothelial dysfunction of arteries. Am J Physiol Heart Circ Physiol 308:H92-100|
|Song, Su; Kertowidjojo, Elizabeth; Ojaimi, Caroline et al. (2015) Long-term methionine-diet induced mild hyperhomocysteinemia associated cardiac metabolic dysfunction in multiparous rats. Physiol Rep 3:|
|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|
|Laurent, D; Mathew, J E; Mitry, M et al. (2014) Chronic ethanol consumption increases myocardial mitochondrial DNA mutations: a potential contribution by mitochondrial topoisomerases. Alcohol Alcohol 49:381-9|
|Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2014) Response to letter regarding article ""Inositol 1,4,5-trisphosphate receptors and human left ventricular myocytes"". Circulation 129:e510-1|
|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|
|Hicks, S; Labinskyy, N; Piteo, B et al. (2013) Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat. Am J Physiol Heart Circ Physiol 304:H903-15|
|Wolin, Michael S (2013) Evidence for novel aspects of Nox4 oxidase regulation of mitochondrial function and peroxide generation in an endothelial cell model of senescence. Biochem J 452:e1-2|
Showing the most recent 10 out of 394 publications