Cardiovascular Medicine Department, the First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China .
J Cardiovasc Pharmacol. 2021 Apr 29;77(6):767-776. doi: 10.1097/FJC.0000000000001030.
Cardiovascular disease ranks the leading cause of mortality worldwide. Prenyldiphosphate synthase subunits collectively participate in the formation and development of atherosclerosis (AS). This study aimed to investigate the role of PDSS2 in AS and its underlying mechanisms. Human coronary artery endothelial cells (HCAECs) were treated with oxidized low-density lipoprotein to establish the AS model. The gene expression levels were determined by qRT-PCR, Western blot, and ELISA. CCK-8, colony formation was applied to determine the proliferation of HCAECs. Chromatin immunoprecipitation assay and luciferase assay were applied to verify the interaction between PDSS2 and Nrf2. The results showed that the serum levels of PDSS2 and Nrf2 were decreased in patients with AS. Overexpression of PDSS2 suppressed the release of reactive oxygen species, iron content and ferroptosis of HCAECs, and promoted the proliferation of HCAECs. Moreover, PDSS2 activated antioxidant Nrf2. PDSS2 interacted with Nrf2 to alleviate the ferroptosis of HCAECs. However, knockdown of Nrf2 alleviated the effects of PDSS2 on the proliferation and ferroptosis of HCAECs. In vivo assays, overexpression of PDSS2 and Nrf2 suppressed the progression of AS. In conclusion, overexpression of PDSS2 suppressed the ferroptosis of HCAECs by promoting the activation of Nrf2 pathways. Thence PDSS2 may play a cardio-protective role in AS.
心血管疾病是全球范围内导致死亡的主要原因。 prenyl diphosphate synthase 亚基共同参与动脉粥样硬化（AS）的形成和发展。本研究旨在探讨 PDSS2 在 AS 中的作用及其潜在机制。用人氧化低密度脂蛋白处理人冠状动脉内皮细胞（HCAEC）建立 AS 模型。通过 qRT-PCR、Western blot 和 ELISA 测定基因表达水平。CCK-8、集落形成实验用于测定 HCAEC 的增殖。应用染色质免疫沉淀实验和荧光素酶实验验证 PDSS2 与 Nrf2 的相互作用。结果表明，AS 患者血清 PDSS2 和 Nrf2 水平降低。PDSS2 的过表达抑制了 HCAEC 中活性氧、铁含量和铁死亡的释放，并促进了 HCAEC 的增殖。此外，PDSS2 激活了抗氧化 Nrf2。PDSS2 与 Nrf2 相互作用，减轻 HCAEC 的铁死亡。然而，Nrf2 的敲低减轻了 PDSS2 对 HCAEC 增殖和铁死亡的影响。在体内实验中，过表达 PDSS2 和 Nrf2 抑制了 AS 的进展。总之，PDSS2 通过促进 Nrf2 通路的激活抑制 HCAEC 的铁死亡，从而在 AS 中发挥心脏保护作用。
