Pu Luya, Meng Qingyu, Li Shuai, Wang Yaru, Liu Bin
Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, China.
Cardiovascular Disease Center, The First Hospital of Jilin University, Changchun, China.
Biochim Biophys Acta Mol Cell Res. 2023 Apr;1870(4):119436. doi: 10.1016/j.bbamcr.2023.119436. Epub 2023 Feb 7.
Atherosclerosis is the main cause of cardiovascular disease, and fluid shear stress is a key factor regulating its occurrence and development. Oscillatory shear stress (Oss) is an important pro-atherosclerosis factor. Oss mainly occurs in areas that are susceptible to atherosclerosis, but the exact mechanism of atherosclerosis induction remains unclear. Therefore, starting from the atheroprone phenotype that Oss stimulates abnormal vascular endothelial cell proliferation, this study aimed to reveal the underlying mechanism of Oss-induced atherosclerosis formation and to identify new targets for the prevention and treatment of atherosclerosis. In this study, the gene encoding thioredoxin reductase 1 (TXNRD1), which is closely related to atherosclerosis development and cell proliferation, was screened by analyzing the transcriptome sequencing data of static and Oss-treated human aortic endothelial cells (HAECs). Moreover, this study successfully verified that TXNRD1 mRNA and protein were significantly upregulated in Oss-treated HAECs. Oss significantly promoted the proliferation, migration, and tube formation of HAECs, whereas TXNRD1 knockdown impaired the proliferation, migration, and tube formation of Oss-treated HAECs, and this process was mainly achieved via activation of the apoptosis pathway. To further clarify whether Oss-sensitive TXNRD1 affects the apoptosis rate and proliferative ability of HAECs by regulating the endothelial nitric oxide synthase (eNOS) pathway, we used NG-nitro-L-arginine methyl ester (L-NAME) to inhibit eNOS activity and nitric oxide (NO) production. L-NAME significantly reversed the promoting effect of TXNRD1 knockdown on Oss-treated HAEC apoptosis, and it also abolished the inhibitory effect of TXNRD1 knockdown on the proliferation and S + G2 phase cell mass of Oss-treated HAECs. In conclusion, this study showed that TXNRD1 knockdown inhibited the proliferation of HAECs exposed to Oss by activating the eNOS/apoptosis pathway, revealing that TXNRD1 is involved in the dysregulation of Oss-induced endothelial cell proliferation. These findings provide new directions and insights into the prevention and treatment of atherosclerosis.
动脉粥样硬化是心血管疾病的主要原因，而流体切应力是调节其发生和发展的关键因素。振荡切应力（Oss）是一种重要的促动脉粥样硬化因子。Oss主要发生在易患动脉粥样硬化的区域，但其诱导动脉粥样硬化的确切机制仍不清楚。因此，本研究从Oss刺激异常血管内皮细胞增殖的易患动脉粥样硬化表型出发，旨在揭示Oss诱导动脉粥样硬化形成的潜在机制，并确定预防和治疗动脉粥样硬化的新靶点。在本研究中，通过分析静态和Oss处理的人主动脉内皮细胞（HAECs）的转录组测序数据，筛选出与动脉粥样硬化发展和细胞增殖密切相关的硫氧还蛋白还原酶1（TXNRD1）编码基因。此外，本研究成功验证了TXNRD1 mRNA和蛋白在Oss处理的HAECs中显著上调。Oss显著促进HAECs的增殖、迁移和管腔形成，而TXNRD1基因敲低则损害了Oss处理的HAECs的增殖、迁移和管腔形成，这一过程主要通过激活凋亡途径实现。为了进一步阐明Oss敏感的TXNRD1是否通过调节内皮型一氧化氮合酶（eNOS）途径影响HAECs的凋亡率和增殖能力，我们使用NG-硝基-L-精氨酸甲酯（L-NAME）抑制eNOS活性和一氧化氮（NO）生成。L-NAME显著逆转了TXNRD1基因敲低对Oss处理的HAECs凋亡的促进作用，同时也消除了TXNRD1基因敲低对Oss处理的HAECs增殖和S+G2期细胞量的抑制作用。总之，本研究表明TXNRD1基因敲低通过激活eNOS/凋亡途径抑制了暴露于Oss的HAECs的增殖，揭示了TXNRD1参与了Oss诱导的内皮细胞增殖失调。这些发现为动脉粥样硬化的预防和治疗提供了新的方向和见解。
