Activation of heme oxygenase and suppression of cGMP are associated with impaired endothelial function in obstructive sleep apnea with hypertension.
BACKGROUND
Obstructive 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.


METHODS
We determined flow-mediated vasodilatation (FMD) as a measure of endothelial-dependent vasodilatory capacity, exhaled CO, bilirubin, and guanosine 3',5'-cyclic monophosphate (cGMP) in 63 subjects with OSA (normotensive 27, hypertensive 36) and in 32 subjects without OSA (normotensive 19, hypertensive 13).


RESULTS
Hypertensive OSA demonstrated marked impairment in FMD (8.0 ± 0.5% vasodilatation) compared to 10.5 ± 0.8% in hypertensives non-OSA (P < 0.01) and 13.5 ± 0.5% in normotensive OSA (P < 0.001) and 16.1 ± 1.1% in normotensive non-OSA (P < 0.0001). HO was upregulated and plasma nitric oxide (NO) was significantly increased in hypertensive OSA compared to normotensive OSA and hypertensive non-OSA. Conversely, serum cGMP was markedly decreased in hypertensive OSA (12.9 ± 1.8 pmol/ml vs. 20.6 ± 3.7 in normotensive OSA, P = 0.032). There was an inverse relationship between FMD and CO and bilirubin concentrations (r = 0.43, P = 0.0001 and r = 0.28, P = 0.01, respectively).


CONCLUSIONS
These data show that increased CO in the setting of elevated NO concentrations is associated with decreased cGMP, impaired FMD, and hypertension in patient with OSA.
Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine and John B. Pierce Laboratory, New Haven, CT, USA.
Behrouz
B
Jafari
Vahid
V
Mohsenin
D001663:Bilirubin / Q000097:blood; D002248:Carbon Monoxide / Q000378:metabolism; D006152:Cyclic GMP / Q000097:blood*; D004789:Enzyme Activation; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000503:physiopathology*; D014664:Vasodilation
D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D006152:Cyclic GMP; D001663:Bilirubin