Ferroptosis due to Cystathionine γ Lyase/Hydrogen Sulfide Downregulation Under High Hydrostatic Pressure Exacerbates VSMC Dysfunction

Ruxi Jin; Ruixue Yang; Changting Cui; Haizeng Zhang; Jun Cai; Bin Geng; Zhenzhen Chen

doi:10.3389/fcell.2022.829316

Ferroptosis due to Cystathionine γ Lyase/Hydrogen Sulfide Downregulation Under High Hydrostatic Pressure Exacerbates VSMC Dysfunction

Front Cell Dev Biol. 2022 Feb 3:10:829316. doi: 10.3389/fcell.2022.829316. eCollection 2022.

Authors

Ruxi Jin¹, Ruixue Yang¹, Changting Cui¹, Haizeng Zhang¹, Jun Cai¹, Bin Geng¹, Zhenzhen Chen¹

Affiliation

¹ State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Hydrostatic pressure, stretch, and shear are major biomechanical forces of vessels and play critical roles in genesis and development of hypertension. Our previous work demonstrated that high hydrostatic pressure (HHP) promoted vascular smooth muscle cells (VSMCs) two novel subsets: inflammatory and endothelial function inhibitory VSMCs and then exacerbated VSMC dysfunction. However, the underlying mechanism remains unknown. Here, we first identified that aortic GPX4 (a core regulator of ferroptosis) significantly downregulated association with VSMC novel phenotype elevation in SHR rats and hypertension patients. In primary VSMCs, HHP (200 mmHg) increased iron accumulation, ROS production, and lipid peroxidation compared with normal pressure (100 mmHg). Consistently, the ferroptosis-related gene (COX-2, TFRC, ACSL4, and NOX-1) expression was also upregulated. The ferroptosis inhibitor ferrostatin-1 (Fer-1) administration blocked HHP-induced VSMC inflammatory (CXCL2 expression) and endothelial function inhibitory (AKR1C2 expression) phenotyping switch association with elevation in the GPX4 expression, reduction in the reactive oxygen species (ROS), and lipid peroxidation production. In contrast, the ferroptosis inducer RLS3 increased HHP-induced CXCL2 and AKR1C2 expressions. These data indicate HHP-triggering ferroptosis contributes to VSMC inflammatory and endothelial function inhibitory phenotyping switch. In mechanism, HHP reduced the VSMC GSH content and cystathionine gamma-lyase (CSE)/hydrogen sulfide (H₂S)-an essential system for GSH generation. Supplementation of the H₂S donor-NaHS increased the VSMC GSH level, alleviated iron deposit, ROS and lipid peroxidation production. NaHS administration rescues both HHP- and RLS3-induced ferroptosis. Collectively, HHP downregulated VSMC CSE/H₂S triggering GSH level reduction, resulting in ferroptosis, which contributed to the genesis of VSMC inflammation and endothelial function inhibitory phenotypes.

Keywords: VSMCs; ferroptosis; hydrogen sulfide; hydrostatic pressure; hypertension.