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

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

doi:10.3389/fcell.2022.829316

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.

Highlights

Biomechanical forces within the vasculature contain wall shear stress, circumferential wall tensile stress, and hydrostatic pressure (Takayama et al, 2013), and these biomechanics contribute to pathogenesis and development of hypertension and its complications (Hayashi and Naiki, 2009)
To investigate ferroptosis involved in HHPinduced vascular smooth muscle cells (VSMCs) novel phenotypes, we measured the glutathione peroxidase 4 (GPX4) protein level
These results indicated that ferroptosis associated with the VSMC phenotype switch in the hypertensive animal model and hypertensive patients

Summary

Introduction

Biomechanical forces within the vasculature contain wall shear stress, circumferential wall tensile stress, and hydrostatic pressure (Takayama et al, 2013), and these biomechanics contribute to pathogenesis and development of hypertension and its complications (Hayashi and Naiki, 2009). The mechanical cyclic stretch force contributes to vascular smooth muscle cell functions (e.g., apoptosis, proliferation, and migration), which is crucial in vascular remodeling during hypertension (Cheng et al, 2012; Qi et al, 2018), whereas little attention is paid to hydrostatic pressure regulation. Recombinant human GPX4 (Liu et al, 2021) and ferroptosis inhibitor Fer-1 (Li et al, 2020) treatment attenuated myocardial injuries. These works indicate that ferroptosis contributes to the pathogenesis of cardiovascular diseases

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