Chronic intermittent hypoxia-induced H2S production promotes carotid body hyperactivity via the upregulation of Sp1 S-sulfhydration and angiotensin II receptor.

Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), induces increased carotid body (CB) activity. Hydrogen sulfide (H2S), a critical oxygen sensor in the CB, promotes protein post-translational modification via S-sulfhydration. This study investigated whether CIH-induced H₂S production drives CB hyperactivity through Sp1 S-sulfhydration-mediated upregulation of angiotensin II receptor type 1 (AT1). Rats were exposed to CIH for 12 weeks. CB activity, H₂S levels, and AT1/Sp1 expression were analyzed. Pharmacological inhibitors [AOAA (H₂S synthase inhibitor) and DTT (S-sulfhydration inhibitor)] and the AT1 antagonist losartan were used in vivo and in PC12 cells under intermittent hypoxia (IH) to elucidate the underlying mechanisms. CIH significantly increased H₂S production and CB hyperactivity, and these effects were reversed by AOAA. Both AOAA and DTT inhibited Sp1 S-sulfhydration and AT1 upregulation in CB tissue and IH-exposed PC12 cells. AT1 inhibition with losartan normalized CB hyperactivity. Mechanistically, H₂S-mediated Sp1 S-sulfhydration enhanced AT1 transcriptional activation, leading to sustained CB sensitization. CIH enhances CB activity through H₂S-dependent Sp1 S-sulfhydration, which increases AT1 expression. This pathway represents a novel therapeutic target for OSA-associated hypertension.