Jin Ruxi, Yang Ruixue, Cui Changting, Zhang Haizeng, Cai Jun, Geng Bin, Chen Zhenzhen
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.
Front Cell Dev Biol. 2022 Feb 3;10:829316. doi: 10.3389/fcell.2022.829316. eCollection 2022.
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 (, , , and ) 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 (HS)-an essential system for GSH generation. Supplementation of the HS 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/HS triggering GSH level reduction, resulting in ferroptosis, which contributed to the genesis of VSMC inflammation and endothelial function inhibitory phenotypes.
流体静压、牵张和剪切力是血管的主要生物力学力，在高血压的发生和发展中起关键作用。我们之前的研究表明，高流体静压（HHP）促进血管平滑肌细胞（VSMC）形成两个新的亚群：炎症性和抑制内皮功能的VSMC，进而加剧VSMC功能障碍。然而，其潜在机制仍不清楚。在此，我们首先发现，主动脉中的谷胱甘肽过氧化物酶4（GPX4，铁死亡的核心调节因子）在自发性高血压大鼠（SHR）和高血压患者中与VSMC新表型升高的相关性显著下调。在原代VSMC中，与正常压力（100 mmHg）相比，HHP（200 mmHg）增加了铁积累、活性氧（ROS）生成和脂质过氧化。一致地，铁死亡相关基因（、、和）的表达也上调。给予铁死亡抑制剂铁抑素-1（Fer-1）可阻断HHP诱导的VSMC炎症（CXCL2表达）和抑制内皮功能（AKR1C2表达）的表型转换，这与GPX4表达升高、活性氧（ROS）减少和脂质过氧化生成有关。相反，铁死亡诱导剂RLS3增加了HHP诱导的CXCL2和AKR1C2表达。这些数据表明，HHP触发的铁死亡促成了VSMC炎症和抑制内皮功能的表型转换。机制上，HHP降低了VSMC的谷胱甘肽（GSH）含量和胱硫醚γ-裂解酶（CSE）/硫化氢（HS）——GSH生成的必需系统。补充HS供体——硫氢化钠（NaHS）可提高VSMC的GSH水平，减轻铁沉积、ROS和脂质过氧化生成。给予NaHS可挽救HHP和RLS3诱导的铁死亡。总体而言，HHP下调VSMC的CSE/HS，触发GSH水平降低，导致铁死亡，这促成了VSMC炎症和抑制内皮功能表型的发生。
