Molecular mechanisms of chronic intermittent hypoxia and hypertension

Abstract

Obstructive sleep apnea (OSA) is characterized by episodes of repeated airway obstruction resulting in cessation (apnea) or reduction (hypopnea) in airflow during sleep. These events lead to intermittent hypoxia and hypercapnia, sleep fragmentation, and changes in intrathoracic pressure, and are associated with a marked surge in sympathetic activity and an abrupt increase in blood pressure. Blood pressure remains elevated during wakefulness despite the absence of obstructive events resulting in a high prevalence of hypertension in patients with OSA. There is substantial evidence that suggests that chronic intermittent hypoxia (CIH) leads to sustained sympathoexcitation during the day and changes in vasculature resulting in hypertension in patients with OSA. Mechanisms of sympathoexcitation include augmentation of peripheral chemoreflex sensitivity and a direct effect on central sites of sympathetic regulation. Interestingly, the vascular changes that occur with CIH have been ascribed to the same molecules that have been implicated in the augmented sympathetic tone in CIH. This review will discuss the hypothesized molecular mechanisms involved in the development of hypertension with CIH, will build a conceptual model for the development of hypertension following CIH, and will propose a systems biology approach in further elucidating the relationship between CIH and the development of hypertension.

FIGURE 1

Molecular mechanism of sensory long-term facilitation (sLTF) and increased hypoxic chemosensitivity of the carotid body following CIH. Chronic intermittent hypoxia leads to an increase in AT1 receptor expression which in turn results in NOX mediated increases in cytosolic and mitochondrial ROS. ROS activates HIF-1 α and induces sLTF in the carotid body through Endothelin 1. (AT1—angiotensin II type 1 receptor; NOX—NADPH oxidase; HIF— hypoxia inducible factor; SOD—super oxide dismutase; ETC—electron transport chain; ROS—reactive oxygen species; ET-1—endothelin 1; ETA—endothelin A receptor; nNOS—neuronal nitric oxide synthase).

FIGURE 2

Putative molecular mechanisms by which CIH induces increases in central sympathetic activation; “?” is used to designate hypothesized mechanism that has not been proven yet. Chronic intermittent hypoxia activates transcription factors such as Delta Fos B within brain regions involved in autonomic control. Additionally CIH induces a pressor response in the RVLM mediated by an AT-1 dependent increase in NOX-derived ROS production. ET1 mediated increases in ETA expression in the CVO, reduction in nNOS in the PVN and HIF-1 mediated increases in HO-1 all play a role in central sympathoexcitation following CIH. (AT1—angiotensin II type 1 receptor; NOX— NADPH oxidase; HIF—hypoxia-inducible factor; HO-1—heme oxygenase-1; ROS—reactive oxygen species; ET-1— endothelin 1; ETA—endothelin A receptor; nNOS—neuronal nitric oxide synthase; CVO—circumventricular organ; PVN—paraventricular nucleus; RVLM—rostralventrolateral medulla).

FIGURE 3

Putative molecular mechanisms by which CIH induces changes in vascular tone, resulting in the development of hypertension; “?” is used to designate hypothesized mechanism that has not been proven yet. Angiotensin II, ET1 and nNOS also play a role in CIH induced vascular changes resulting in hypertension. NFATc3, a nuclear factor involved in maintenance of vascular smooth muscle reactivity appears to be downstream of ET1 and appears to be important in the vascular changes and hypertension induced by CIH. (AT1—angiotensinII type 1 receptor; NOX—NADPH oxidase; ROS—reactive oxygen species; ET-1—endothelin 1; ETA—endothelin A receptor; nNOS— neuronal nitric oxide synthase; NFATc3—nuclear activator of T cells).