Recent studies from this laboratory have suggested that in both atherosclerosis and hypertension, the function of the endothelial nitric oxide synthase (eNOS) is altered such that it produces superoxide rather than nitric oxide (NO). This phenomenon has been referred to as eNOS """"""""uncoupling"""""""". Preliminary studies indicate that peroxynitrite, formed by the reaction between superoxide and nitric oxide, oxidizes tetrahydrobiopterin (BH4), a critical co-factor of eNOS, and that this leads to uncoupling of the enzyme in vivo. Under normal conditions a major source of reactive oxygen species in the endothelium is the NADPH oxidase which by producing superoxide could participate in peroxynitrite production. The project is to test the hypothesis that hypertension may initially stimulate NADPH oxidase to produce """"""""kindling radicals"""""""" (in particular peroxynitrite), that in turn oxidize tetrahydrobiopterin and uncouple eNOS.
In aim 1, DOCA-salt hypertension will be created in gp91phox mice. These animals lack NADPH oxidase activity in the endothelium and eNOS will not be uncoupled.
In aim 2, to prevent eNOS uncoupling, DOCA-salt hypertensive rats will be treated with ebselen, a potent peroxynitrite scavenger and oral BH4, either alone or in combination. The effect of these interventions on vascular and endothelial BH4 levels will be determined.
In aim 3, the role of endothelial and eNOS-derived hydrogen peroxide on vascular hypertrophy will be determined using DOCA-salt hypertension mice that overexpress catalase in the endothelium and are deficient in eNOS.
Aim 4 is to define the enzymatic source involved in oscillatory shear-induced superoxide production by cultured endothelial cells using electron spin resonance.
| Norlander, Allison E; Madhur, Meena S; Harrison, David G (2018) The immunology of hypertension. J Exp Med 215:21-33 |
| Tran, Anh Nhat; Walker, Kiera; Harrison, David G et al. (2018) Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance. Neuro Oncol 20:1055-1067 |
| Pandey, Arvind K; Singhi, Eric K; Arroyo, Juan Pablo et al. (2018) Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease. Hypertension 71:e1-e8 |
| Loperena, Roxana; Van Beusecum, Justin P; Itani, Hana A et al. (2018) Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide. Cardiovasc Res 114:1547-1563 |
| Dikalova, Anna E; Itani, Hana A; Nazarewicz, Rafal R et al. (2017) Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension. Circ Res 121:564-574 |
| Foss, Jason D; Kirabo, Annet; Harrison, David G (2017) Do high-salt microenvironments drive hypertensive inflammation? Am J Physiol Regul Integr Comp Physiol 312:R1-R4 |
| Guzik, Tomasz J; Skiba, Dominik S; Touyz, Rhian M et al. (2017) The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res 113:1009-1023 |
| Grome, Heather N; Barnett, Louise; Hagar, Cindy C et al. (2017) Association of T Cell and Macrophage Activation with Arterial Vascular Health in HIV. AIDS Res Hum Retroviruses 33:181-186 |
| Loperena, Roxana; Harrison, David G (2017) Oxidative Stress and Hypertensive Diseases. Med Clin North Am 101:169-193 |
| Oh, Young S; Berkowitz, Dan E; Cohen, Richard A et al. (2017) A Special Report on the NHLBI Initiative to Study Cellular and Molecular Mechanisms of Arterial Stiffness and Its Association With Hypertension. Circ Res 121:1216-1218 |
Showing the most recent 10 out of 141 publications
