title: Endothelial nitric oxide synthase uncoupling: a novel pathway in OSA induced vascular endothelial dysfunction.
abstract: The mechanism of vascular endothelial dysfunction (VED) and cardiovascular disease in obstructive sleep apnea (OSA) is unknown. We performed a comprehensive evaluation of endothelial nitric oxide synthase (eNOS) function directly in the microcirculatory endothelial tissue of OSA patients who have very low cardiovascular risk status. Nineteen OSA patients underwent gluteal biopsies before, and after effective treatment of OSA. We measured superoxide (O2(•-)) and nitric oxide (NO) in the microcirculatory endothelium using confocal microscopy. We evaluated the effect of the NOS inhibitor l-Nitroarginine-Methyl-Ester (l-NAME) and the NOS cofactor tetrahydrobiopterin (BH4) on endothelial O2(•-) and NO in patient endothelial tissue before and after treatment. We found that eNOS is dysfunctional in OSA patients pre-treatment, and is a source of endothelial O2(•-) overproduction. eNOS dysfunction was reversible with the addition of BH4. These findings provide a new mechanism of endothelial dysfunction in OSA patients and a potentially targetable pathway for treatment of cardiovascular risk in OSA.
authors.affiliation: The Sleep Heart Program, the Ohio State University, Columbus, OH, United States; Division of Pulmonary Critical Care and Sleep, The Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, the Ohio State University, Columbus, OH, United States.
authors.forename: Saradhadevi
authors.initials: S
authors.lastname: Varadharaj
authors.affiliation: The Center for Biostatistics, the Ohio State University, Columbus, OH, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: Porter
authors.affiliation: The Sleep Heart Program, the Ohio State University, Columbus, OH, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Pleister
authors.affiliation: The Sleep Heart Program, the Ohio State University, Columbus, OH, United States.
authors.forename: Jacob
authors.initials: J
authors.lastname: Wannemacher
authors.affiliation: The Sleep Heart Program, the Ohio State University, Columbus, OH, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Sow
authors.affiliation: The Sleep Heart Program, the Ohio State University, Columbus, OH, United States.
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.affiliation: The Sleep Heart Program, the Ohio State University, Columbus, OH, United States; Division of Pulmonary Critical Care and Sleep, The Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, the Ohio State University, Columbus, OH, United States.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.affiliation: The Sleep Heart Program, the Ohio State University, Columbus, OH, United States; Division of Pulmonary Critical Care and Sleep, The Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, the Ohio State University, Columbus, OH, United States. Electronic address: rami.khayat@osumc.edu.
authors.forename: Rami N
authors.initials: RN
authors.lastname: Khayat
mesh_terms: D000328:Adult; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000209:etiology*; D045422:Continuous Positive Airway Pressure / Q000379:methods; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D020181:Sleep Apnea, Obstructive / Q000150:complications* / Q000473:pathology* / Q000628:therapy
chemical_list: D004791:Enzyme Inhibitors; D001708:Biopterins; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D019331:NG-Nitroarginine Methyl Ester
keywords: Endothelial dysfunction; Hypertension; Nitric oxide; Obstructive sleep apnea