Abstract 19768: eNOS Uncoupling Leads to Endothelial Dysfunction in Clinical Obstructive Sleep Apnea (OSA): Role of BH4 Depletion

Abstract

OSA is increasingly recognized as a cardiovascular risk factor and is a cause of hypertension, worsening coronary disease and heart failure. OSA leads to endothelial dysfunction (ED) and decreased Nitric oxide (NO) availability. The mechanism of ED in OSA remains unknown. We previously found that OSA causes increased peroxynititrite production in the endothelium. We hypothesized that increased peroxynitrite would result in oxidative modification of proteins and decreased BH4 availability. Methods: Participants were 13 patients with recently diagnosed OSA and 10 healthy individuals with low cardiovascular risk. OSA Patients underwent subcutaneous forearm biopsy and doppler measurements of endothelial function by flow mediated dilation (FMD) prior to, and 12 weeks after initiation of treatment. Non-OSA controls also had FMD measurements and biopsies. NO and superoxide ( · O 2 _ ) levels in the microcirculation were determined using fluorescent probes CuFL and DHE respectively in the absence or presence of the NO synthase inhibitor, L-NAME, the NO scavenger, PTIO, and the SOD mimetic, MnTBAP. Results: OSA patients had impaired FMD, compared to non-OSA controls, which decreased after 12 weeks of CPAP treatment. OSA patients had increased endothelial · O 2 _ and decreased NO production compared to controls. CPAP treatment decreased · O 2 _ and increased NO production in OSA patients. Incubation of subcutaneous sections with BH4 resulted in a significant increase in NO and decrease in · O 2 _ production in the endothelial tissue of untreated OSA patients. The BH4 effect on · O 2 _ and NO was more in OSA patients before treatment than after treatment (Figure). This indicates BH4 deficiency is important for VED in OSA patients. Conclusions: Thus BH4 deficiency occurs in VED in OSA and BH 4 supplementation can restore eNOS function conferring protection with reduced oxidative stress. Future clinical studies are warranted to evaluate BH4 supplementation in normalization of ED in OSA.