Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, Affiliated To Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Cardiovasc Transl Res. 2022 Oct;15(5):1010-1023. doi: 10.1007/s12265-022-10230-3. Epub 2022 Apr 4.
Abnormal function of endothelial cells (ECs) is an important reason for vascular endothelial remodeling and atherosclerotic plaque formation in patients with atherosclerosis (AS). Here, we report for the first time that the vascular ECs with apoptosis resistance phenotype (ARECs) exist in peripheral blood of AS patients. Our research data showed that the switch of regulation modes between HIF-1α and Bax operated by lncRNA-ASLNC18810 is the direct cause for the formation of ARECs. When ASLNC18810 is low or missing, HIF-1α indirectly negatively regulates the Bax in post-transcription through HIF-1α/miR-559/Bax pathway which makes ECs acquire apoptosis resistance and form ARECs. The functional experiments results showed that ASLNC18810 could effectively eliminate the anti-apoptotic properties of ARECs by blocking the HIF-1α/miR559/Bax pathway and maintaining HIF-1α/Bax pathway. In a word, our study shows that ASLNC18810 has full potential to become a biological target for the prevention and treatment of atherosclerotic plaques by regulating ARECs. ASLNC18810 was significantly upregulated in ECs compared to ARECs. With high level of ASLNC18810 in ECs, ASLNC18810 binds to miR-559 as a miRNA sponge and suppresses the inhibition effect of miR-559 on Bax protein, this direct positive transcriptional regulation between HIF-1α and Bax endows the apoptotic property in ECs induced by Ox-LDL. However, with low expression of ASLNC18810 in ARECs, the post-transcriptional regulation of Bax by miR-559 dominates and the indirect negative regulation between HIF-1α and Bax endows the anti-apoptotic property of ARECs. To sum up, low ASLNC18810 expression-mediated switching of HIF-1α/Bax pathway to HIF-1α/miR-559/Bax pathway is the internal reason for ECs to obtain apoptosis resistance and the formation of ARECs under the ox-LDL induction.
内皮细胞（ECs）的异常功能是动脉粥样硬化（AS）患者血管内皮重塑和动脉粥样硬化斑块形成的重要原因。在这里，我们首次报道在 AS 患者的外周血中存在抗凋亡表型的血管 ECs（ARECs）。我们的研究数据表明，lncRNA-ASLNC18810 介导的 HIF-1α 和 Bax 之间调控模式的转换是 ARECs 形成的直接原因。当 ASLNC18810 低表达或缺失时，HIF-1α 通过 HIF-1α/miR-559/Bax 通路间接负调控 Bax 的转录后水平，使 ECs 获得抗凋亡能力并形成 ARECs。功能实验结果表明，ASLNC18810 通过阻断 HIF-1α/miR559/Bax 通路并维持 HIF-1α/Bax 通路，可有效消除 ARECs 的抗凋亡特性。总之，我们的研究表明，ASLNC18810 通过调节 ARECs 具有成为预防和治疗动脉粥样硬化斑块的生物学靶标的潜力。ASLNC18810 在 ECs 中的表达水平明显高于 ARECs。在 ECs 中高水平的 ASLNC18810 与 miR-559 结合作为 miRNA 海绵，抑制 miR-559 对 Bax 蛋白的抑制作用，HIF-1α 和 Bax 之间的这种直接正向转录调控赋予了 Ox-LDL 诱导的 ECs 的凋亡特性。然而，在 ARECs 中 ASLNC18810 低表达时，miR-559 对 Bax 的转录后调控占主导地位，HIF-1α 和 Bax 之间的间接负调控赋予了 ARECs 的抗凋亡特性。总之，低表达的 ASLNC18810 介导的 HIF-1α/Bax 通路向 HIF-1α/miR-559/Bax 通路的转换是 ECs 在 ox-LDL 诱导下获得抗凋亡能力并形成 ARECs 的内在原因。
