![]() Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BH4. Dumitrescu C, Biondi R, Xia Y, Cardounel AJ, Druhan LJ, Ambrosio G, Zweier JL. HPLC analysis of tetrahydrobiopterin and its pteridine derivatives using sequential electrochemical and fluorimetric detection: application to tetrahydrobiopterin autoxidation and chemical oxidation. Biondi R, Ambrosio G, De Pascali F, Tritto I, Capodicasa E, Druhan LJ, Hemann C, Zweier JL. The cytotoxic potential of superoxide and nitric oxide. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Incalza MA, D'Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F. Oxidative stress, antioxidants, and endothelial function. Endothelial nitric oxide synthase and endothelial dysfunction. Endothelial dysfunction and vascular disease - a 30th anniversary update. Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation. Halcox JP, Narayanan S, Cramer-Joyce L, Mincemoyer R, Quyyumi AA. Cytoglobin regulates blood pressure and vascular tone through nitric oxide metabolism in the vascular wall. Liu XP, El-Mahdy MA, Boslett J, Varadharaj S, Hemann C, Abdelghany TM, Ismail RS, Little SC, Zhou D, Thuy LTT, Kawada N, Zweier JL. ![]() Regulation of nitric oxide metabolism and vascular tone by cytoglobin. Nitric oxide synthase is a cytochrome-P-450 type hemoprotein. Nitric oxide: physiology, pathophysiology, and pharmacology. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. This process is progressive, increasing with the duration of e-cig exposure, and is more severe in the presence of nicotine, but observed even with nicotine-free vaping. ![]() e-cig exposure activates and increases expression of NADPH oxidase and disrupts activation and coupling of eNOS, leading to a vicious cycle of superoxide generation and peroxynitrite formation, with tetrahydrobiopterin depletion, causing loss of NO that triggers vascular endothelial dysfunction. NEW & NOTEWORTHY Underlying mechanisms of e-cig-induced vascular endothelial dysfunction are delineated. Together, our data demonstrate that ECV exposure activates NADPH oxidase and uncouples eNOS, causing a vicious cycle of superoxide generation and vascular oxidant stress that triggers VED and hypertension with predisposition to other cardiovascular disease. NADPH oxidase and NOS inhibitors abrogated ECV-induced superoxide generation in the aorta of ECV-exposed mice. Following ECV exposure, the critical NOS cofactor tetrahydrobiopterin was decreased, with a concomitant loss of its salvage enzyme, dihydrofolate reductase. Downregulation of endothelial nitric oxide synthase (eNOS) expression and Akt-dependent eNOS phosphorylation occurred in the aorta of ECV-exposed mice, indicating that exposure inhibited de novo NO synthesis. Exposure increased NADPH oxidase expression, supporting its role in ECV-induced superoxide generation. Decreased intravascular nitric oxide (NO) levels and increased superoxide generation with elevated 3-nitrotyrosine levels in the aorta of ECV-exposed mice were observed, indicating that ECV-induced superoxide reacts with NO to generate cytotoxic peroxynitrite. Time-dependent elevation in blood pressure and systemic vascular resistance were observed, along with an impairment of acetylcholine-induced aortic relaxation in ECV-exposed mice, compared with air-exposed control. C57/BL6 male mice were exposed to ECV generated from e-cig liquid containing 0, 6, or 24 mg/mL nicotine for 16 and 60 wk. Here, we delineate the underlying mechanisms of ECV-induced vascular endothelial dysfunction (VED), a central trigger of cardiovascular disease. We recently reported a mouse model of chronic electronic cigarette (e-cig) exposure-induced cardiovascular pathology, where long-term exposure to e-cig vape (ECV) induces cardiac abnormalities, impairment of endothelial function, and systemic hypertension.
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