Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China.
Department of Cardiology, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Cell Death Dis. 2024 Sep 20;15(9):689. doi: 10.1038/s41419-024-07086-7.
Recent research has explored the potential of the demethylating drug 5-azacytidine (Aza) as therapy for a range of diseases. However, the therapeutic efficacy of Aza for patients of atherosclerosis remains unclear. This study investigates the therapeutic application of Aza to atherosclerosis in order to elucidate the underlying mechanisms. We generated induced Tregs (iTregs) from CD4 T cells by using Aza in vitro, and this was followed by the intravenous infusion of iTregs for the treatment of atherosclerosis. The adoptive transfer of Aza-iTreg significantly increased peripheral blood Treg cells, suppressed inflammation, and attenuated atherosclerosis in ApoE mice. Furthermore, we observed a notable demethylation of the Forkhead box P3 (Foxp3)-regulatory T cell-specific demethylated region (TSDR) and an upregulation of Foxp3 expression in the CD4 T cells in the spleen of the ApoE mice following the transfer of Aza- iTregs. We also demonstrated that Aza converted naive CD4 T cells into Tregs by DNA methyltransferase 1 (Dnmt1)-mediated Foxp3-TSDR demethylation and the upregulation of Foxp3 expression. Conversely, the overexpression of Dnmt1 in the CD4 T cells attenuated the Aza-induced Foxp3-TSDR demethylation and upregulation of Foxp3 expression. Our results reveal that Aza converts naive CD4 T cells into functional Tregs by inhibiting Dnmt1, and the transfer of Aza-iTregs suppresses atherosclerosis in mice.
最近的研究探索了去甲基化药物 5-氮杂胞苷（Aza）作为治疗一系列疾病的潜在用途。然而，Aza 对动脉粥样硬化患者的治疗效果尚不清楚。本研究旨在探讨 Aza 在动脉粥样硬化治疗中的应用，以阐明其潜在机制。我们通过体外使用 Aza 从 CD4 T 细胞中诱导产生调节性 T 细胞（iTreg），然后通过静脉输注 iTreg 治疗动脉粥样硬化。过继转移 Aza-iTreg 可显著增加外周血 Treg 细胞，抑制炎症反应，并减轻 ApoE 小鼠的动脉粥样硬化。此外，我们观察到，在 ApoE 小鼠中，过继转移 Aza-iTreg 后，Foxp3 调节性 T 细胞特异性去甲基化区（TSDR）在 CD4 T 细胞中的显著去甲基化，以及 Foxp3 表达上调。我们还证明，Aza 通过 DNA 甲基转移酶 1（Dnmt1）介导的 Foxp3-TSDR 去甲基化和 Foxp3 表达上调，将幼稚 CD4 T 细胞转化为 Treg。相反，CD4 T 细胞中 Dnmt1 的过表达减弱了 Aza 诱导的 Foxp3-TSDR 去甲基化和 Foxp3 表达上调。我们的研究结果表明，Aza 通过抑制 Dnmt1 将幼稚 CD4 T 细胞转化为功能性 Treg，过继转移 Aza-iTreg 可抑制小鼠动脉粥样硬化的发生。
