Angiotensin II downregulates vascular endothelial cell hydrogen sulfide production by enhancing cystathionine γ-lyase degradation through ROS-activated ubiquitination pathway

Abstract

The interactions between vasoactive peptides and gasotransmitters have attracted considerable attention from scientists. However, the impact of angiotensin II (AngII) on the endogenous hydrogen sulfide/cystathionine γ-lyase (H₂S/CSE) pathway in vascular endothelial cells remains unclear. In this study, we found, for the first time, that AngII downregulated the endogenous H₂S/CSE pathway in a time-dependent manner. Mechanistically, AngII accelerated the degradation of the CSE protein and shortened its half-life in endothelial cells. AngII significantly induced Lys48 (K48)-linked CSE ubiquitination and subsequent CSE degradation but did not affect Lys63 (K63)-linked CSE ubiquitination in vascular endothelial cells. Treatment with the proteasome inhibitor MG132 and mutation of Lys48 to Arg in ubiquitin successfully blunted the inhibitory effects of AngII on the endogenous H₂S/CSE pathway in vascular endothelial cells. Furthermore, we found that superoxide anion levels were significantly increased in AngII-treated endothelial cells compared with controls and that the ROS scavenger N-acetyl-l-cysteine (NAC) significantly abolished CSE ubiquitination. Taken together, our data suggested that AngII inhibited endogenous H₂S generation through ubiquitination-mediated CSE degradation via the ROS pathway in vascular endothelial cells.

Keywords: AngII; Hydrogen sulfide; Superoxide; Ubiquitin; Vascular endothelial cell.