Accumulating evidence suggests that oxidant stress contributes to the pathogenesis of hypertension and atherosclerosis. Vascular NAD(P)H oxidases are activated in hypertension, predominantly contribute to vascular production of reactive oxygen species (ROS). Indeed, scavenging of ROS with either antioxidant enzymes or inhibitors of vascular NAD(P)H oxidases significantly restores endothelial function to reduce blood pressure. Nevertheless, these treatments failed to completely normalize endothelial function or blood pressure, implicating involvement of other mechanisms that are not readily reversible by scavenging ROS. Recent studies demonstrated that in atherosclerotic or hypertensive blood vessels, endothelial nitric oxide synthase (eNOS) transformed from an antioxidant enzyme into a pro-oxidant enzyme producing ROS rather than nitric oxide. 1 of the causes for this uncoupling of eNOS seems to be a deficiency in eNOS cofactor tetrahydrobiopterin (H4B). It is interesting to speculate that unsatisfactory outcomes of some antioxidant therapies are partially due to their ineffectiveness in recoupling eNOS. The precise mechanisms as to how H4B becomes persistently deficient under disease conditions remain unclear. We and others have recently shown that angiotensin II uncouples eNOS in vitro and in vivo (Figures 1-3, Mollnau et al Cir Res 90: E58-65). In this project we will fully characterize this phenomenon and determine whether it is mediated by vascular NAD(P)H oxidase-derived hydrogen peroxide and an endothelial H4B deficiency (aim 1).
In aim 2 we will determine whether angiotensin II modulation of endothelial H4B salvage enzymes contributes to endothelial H4B deficiency. Effects on eNOS recoupling, endothelial function and blood pressure of H4B precursors/analogues, inhibition of vascular NAD(P)H oxidases, overexpression of H4B salvage enzymes or combination of 2 or more will be studied in angiotensin II infused mice.
In aim 3 we will examine potential roles of eNOS monomerization, threonine phosphorylation and dissociation from heat shock protein 90 (HSP90) in angiotensin II uncoupling of eNOS and their interdependence with H4B deficiency. Effects on eNOS recoupling of agents promoting eNOS dimerization and its association with HSP90 will be studied. These proposed experiments could ultimately lead to novel therapeutics restoring nitric oxide production from uncoupled eNOS, which are anticipated to reduce blood pressure and impede atherosclerosis. We will also determine whether eNOS uncoupling augments hypertension (aim 4, H4B-deficient hph-1 mice will be studied). This will address the question: is eNOS uncoupling a mere consequence/marker of hypertension or 1 of the causes?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Lin, Michael
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhang, Yixuan; Liu, Norika Mengchia; Wang, Yongchen et al. (2017) Endothelial cell calpain as a critical modulator of angiogenesis. Biochim Biophys Acta Mol Basis Dis 1863:1326-1335
Cai, Hua; Wang, Chen (2017) Surviving With Smog and Smoke: Precision Interventions? Chest 152:925-929
Cai, Hua; Wang, Chen (2017) Graphical review: The redox dark side of e-cigarettes; exposure to oxidants and public health concerns. Redox Biol 13:402-406
Zhang, Yixuan; Li, Qiang; Youn, Ji Youn et al. (2017) Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells: IMPLICATIONS IN VEGF-DEPENDENT ANGIOGENESIS AND DIABETIC WOUND HEALING. J Biol Chem 292:407-416
Siu, Kin Lung; Li, Qiang; Zhang, Yixuan et al. (2017) NOX isoforms in the development of abdominal aortic aneurysm. Redox Biol 11:118-125
Liu, Norika Mengchia; Siu, Kin Lung; Youn, Ji Youn et al. (2017) Attenuation of neointimal formation with netrin-1 and netrin-1 preconditioned endothelial progenitor cells. J Mol Med (Berl) 95:335-348
Zhang, Yixuan; Cai, Hua (2017) Editorial commentary: Endothelial-to-mesenchymal transition: When the good one goes bad. Trends Cardiovasc Med 27:394-396
Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49
Siu, Kin Lung; Gao, Ling; Cai, Hua (2016) Differential Roles of Protein Complexes NOX1-NOXO1 and NOX2-p47phox in Mediating Endothelial Redox Responses to Oscillatory and Unidirectional Laminar Shear Stress. J Biol Chem 291:8653-62
Wu, Jing; Saleh, Mohamed A; Kirabo, Annet et al. (2016) Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest 126:50-67

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