MECHANISMS OF H 2 S ACTIVATION BY INTERMITTENT HYPOXIA

H 2 S generated by the enzyme cystathionine‐ϒ‐lyase (CSE) is important for the carotid body activation by hypoxia. Chronic intermittent hypoxia (CIH) is a hallmark manifestation of sleep apnea. An enhanced carotid body chemoreflex has been implicated in causing sympathetic activation and hypertension in sleep apnea patients and in CIH treated rodents. Rodents exposed to CIH exhibit markedly increased carotid body response to hypoxia, which was attributed to increased generation of reactive oxygen species (ROS). But, how ROS mediates the carotid body activation by CIH is not known. We tested the hypothesis that CIH‐induced ROS activates CSE‐derived H 2 S production in the carotid body. Experiments were performed on adult rats, wild‐type and CSE null mice exposed to CIH for 10 days. H 2 S levels were markedly elevated in CBs of CIH treated rats and wild‐type mice. This effect was absent in rats treated with L‐propargyl glycine, an inhibitor of CSE and in mice deficient in CSE. These findings suggested that CIH increases H 2 S production by activating CSE. MnTMPyP, a ROS scavenger also blocked CIH‐induced H 2 S generation, suggesting that ROS activates CSE. However, studies on human embryonic kidney cells (HEK)‐293 cells heterologously expressing CSE showed that CSE is not a direct target of ROS. Instead, IH‐induced ROS inactivates heme oxygenase‐2, an enzyme that generates carbon monoxide (CO) by interfering with Cys 265 (C265A) residue in the heme regulatory motif of the enzyme. As a consequence, maximal CO synthesis (V max ) is reduced leading to decreased CO generation. The reduced CO generation in turn activates CSE by inhibiting the serine phosphorylation and thus increases H 2 S production. (Supported by NIH‐PO1‐HL90554). Support or Funding Information NIH‐PO1‐HL90554