H ₂ S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea

Abstract

Sleep apnea is a prevalent respiratory disease in which episodic cessation of breathing causes intermittent hypoxia. Patients with sleep apnea and rodents exposed to intermittent hypoxia exhibit hypertension. The carotid body senses changes in blood O2 concentrations and an enhanced carotid body chemosensory reflex contributes to hypertension in sleep apnea patients. Using a rodent model of intermittent hypoxia that simulates blood O2-saturation profiles of patients with sleep apnea, increased generation of reactive oxygen species (ROS) in the carotid body has been shown to enhance the chemosensory reflex and trigger hypertension. Here, we report that ROS inhibited CO generation by heme oxygenase-2 (HO-2), a process that requires Cys265 in the heme regulatory motif of HO-2. CO binds to guanylate cyclase to increase production of cGMP, which stimulates protein kinase G-dependent phosphorylation and inactivation of the H2S-producing enzyme cystathionine-γ-lyase (CSE). We showed that ROS induced by intermittent hypoxia inhibited CO production and increased H2S concentrations, which stimulated carotid body neural activity. Blockade of H2S synthesis by CSE either by pharmacological or genetic approaches inhibited carotid body activation and hypertension induced by intermittent hypoxia. Thus, oxidant-induced inactivation of HO-2 leading to increased CSE-dependent H2S production in the carotid body is a critical trigger of hypertension in rodents exposed to intermittent hypoxia.

Toward Hydrogen Sulfide Based Therapeutics: Critical Drug Delivery and Developability Issues

“…However, research in recent years has convincingly demonstrated the role of H 2 S as an endogenous gasotransmitter with importance on par with that of nitric oxide (NO) and carbon monoxide (CO) . H 2 S has been shown to have anti‐inflammation, antitumor, ion channel regulation, cardiovascular protection, and antioxidation effects . Along with these physiological roles, H 2 S is emerging as a potential therapeutic agent much the same way as NO and CO …”

Carotid body chemoreflex: a driver of autonomic abnormalities in sleep apnoea

“…The role of CO-H 2 S signaling in IH-evoked carotid body activation was examined (Yuan et al , 2016). This study showed that ROS generated during IH inhibits HO-2-dependent CO generation and this effect requires Cys 265 in the heme regulatory motif of HO-2.…”

“…The decreased CO in turn increases H 2 S production by activating CSE. Inhibiting CSE-derived H 2 S synthesis either by genetic knock down of CSE or by pharmacological blockade prevents the chemo- reflex activation and hypertension in IH treated rats (Yuan et al , 2016). These findings demonstrate that ROS is epistatic to H 2 S in driving chemo-reflex-dependent hypertension by IH (Fig.…”

“…Anti-oxidants must be administered during the entire duration of IH exposure in order to normalize carotid body function and hypertension, and when given after the onset of heightened chemo-reflex they are totally ineffective in normalizing carotid body function (Peng et al , 2003). A recent study by Yuan et al (2016) showed that systemic administration of L-propargyl glycine (L-PAG, 30 mg/kg; IP), an inhibitor of CSE-dependent H 2 S synthesis given after the onset of IH-induced hypertension normalizes the carotid body activity, sympathetic nerve activity and blood pressure. Thus, inhibitors of CSE-derived H 2 S synthesis may be a novel approach to treat chemo-reflex driven hypertension in patients with sleep apnea.…”

An H2S‐Sensing/CO‐Releasing Flavonol That Operates via Logic Gates

“…[11–13] Perturbations in CO and H 2 S interplay are associated with sleep apnea and other (patho)physiological conditions. [12,14] Currently, there is limited knowledge of the interplay of CO and H 2 S and no molecular tools are available to study their interactions. This arena differs from that of NO/H 2 S interactions wherein a significant body of research is available.…”