Activation of Heme Oxygenase and Suppression of cGMP Are Associated With Impaired Endothelial Function in Obstructive Sleep Apnea With Hypertension

Abstract

Obstructive sleep apnea (OSA) is a highly prevalent disorder characterized by recurrent upper airway obstruction during sleep. These episodes are terminated by arousals and are commonly associated with hypoxemia. The acute hemodynamic and autonomic perturbations that accompany obstructive apneas can lead to sustained diurnal hypertension. [1][2][3] In a cross-sectional study of a sleep clinic patients 60% of men and women with severe OSA had hypertension. 4 In populationbased prospective studies, patients with severe OSA had three times the risk of developing hypertension within 5 years, independent of other risk factors. 1 Current evidence suggests that sympathoexcitation, inflammatory processes, oxidative stress, and endothelial dysfunction play important roles in the pathogenesis of hypertension and vascular complications in OSA. [5][6][7][8][9] However, the exact mechanisms of hypertension and varying susceptibility to endothelial dysfunction among patients with OSA are not well understood.Endothelial-dependent vasodilatory capacity is primarily regulated by local production of nitric oxide (NO) and modulated by carbon monoxide (CO). 10-12 CO is predominantly released during heme metabolism by heme oxygenase (HO), generating iron and biliverdin. Biliverdin is further metabolized to bilirubin by biliverdin reductase. HO has been reported to be present in all tissues and colocalizes with NO synthase in the vasculature. 13,14 Like NO, the ability of CO to relax blood vessels occurs through soluble guanylate cyclase with increases in guanosine 3′,5′-cyclic monophosphate (cGMP) and activation of calcium-gated potassium channels. 15,16 The activation of potassium channels inhibits calcium entry from BackgroundObstructive sleep apnea (Osa) is a highly prevalent disorder that increases the risk of systemic hypertension and cardiovascular diseases. Heme oxygenase (HO) has been shown to be upregulated in patients with Osa and its overexpression in mice causes hypertension. End products of HO are carbon monoxide (CO) and bilirubin. CO exerts a pleiotropic action on vasoregulation. Despite high prevalence and incident of hypertension in Osa, its pathophysiology is not well-understood, particularly in regard to varying susceptibility of patients to hypertension. We investigated the role of HO in endothelial dysfunction and hypertension in Osa.

Review of and Updates on Hypertension in Obstructive Sleep Apnea

“…In addition, sleep deprivation can independently induce systemic inflammation [91, 92]. The synergistic combination of recurrent hypoxemia and sleep deprivation in OSAS patients may cause increased production of inflammatory mediators, upregulation of leucocyte adhesion molecules [93–95], serum amyloid A [96], CRP [97, 98], circulating angiogenic inhibitors [99, 100], and decreased cGMP [101], predisposing OSAS patients to endothelial injury and dysfunction, vasoconstriction, and subsequent vascular events, Figure 1.…”

Endothelial dysfunction and hypertension in obstructive sleep apnea – Is it due to intermittent hypoxia?

“…The subjects are a subset of a cohort that has been published previously. 25 We studied hypertensive and normotensive OSA as well as hypertensive and normotensive non-OSA patients. Hypertension was defined by blood pressure !…”

“…Endothelial function was assessed by a standard flowmediated vasodilation (FMD) method using Doppler ultrasound of the brachial artery between 10 am and 3 pm. 25 In order to best visualize the brachial artery, the arm was comfortably immobilized in the extended position, and the brachial artery was scanned in the longitudinal section 3e5 cm above the antecubital fossa. Gain and depth settings were optimized to identify the lumen-vessel wall interface.…”

Increased Plasma YKL-40/Chitinase-3-Like-Protein-1 Is Associated with Endothelial Dysfunction in Obstructive Sleep Apnea

“…Patients with newly diagnosed and untreated moderate to severe OSA (apnea-hypopnea index, AHI ≥20 events/hr) with and without hypertension were enrolled. The subjects are a subset of a cohort that has been published previously [27]. Hypertension was defined by blood pressure ≥140 mm Hg systolic and/or ≥90 mm Hg diastolic, which had been previously documented by using appropriate sized cuff and measurements that had been made at least in three different occasions according to the standard criteria [28].…”

“…Endothelial function was assessed by a standard flow-mediated vasodilation (FMD) method using Doppler ultrasound of the brachial artery between 9 am and 12 noon as previously described [27]. Subjects had refrained from smoking or consumption of caffeine-containing beverages and fasting for 12 hours prior to the study.…”