Department of Cardiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China.
Department of Ultrasonography, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Transplant. 2023 Jan-Dec;32:9636897231198167. doi: 10.1177/09636897231198167.
Peripheral arterial disease (PAD), characterized by atherosclerosis of the peripheral arteries or even amputation, has threatened public life and health. However, the underlying mechanism remains largely obscure. SUV39H1, a histone methyltransferase, could specifically methylate lysine 9 of histone H3 and act as a repressor in transcriptional activity. The study aimed to investigate the role of SUV39H1 in limb ischemia. C57BL/6 male mice were randomly divided into Sham or Model groups to investigate the expression of SUV39H1 in the ischemic limbs. Then, pharmaceutical inhibition or genetic deletion of SUV39H1 in the limb ischemia mice model was performed to confirm its effect on limb ischemia. The blood perfusion was quantified by laser speckle contrast imaging (LSCI). Capillary density and muscle edema were measured by CD31 immunohistochemical staining and HE staining. The expressions of SUV39H1 and Catalase were confirmed by western blot. Transcriptome sequencing of siSUV39H1 in human umbilical vein endothelial cells (HUVECs) was used to explore the regulation mechanism of SUV39H1 on angiogenesis. The results showed that SUV39H1 was highly expressed in the ischemic muscle tissue of the mice. Pharmaceutical inhibition or genetic deletion of SUV39H1 significantly improved blood perfusion, capillary density, and angiogenesis in ischemic muscle tissue. Cell experiments showed that SUV39H1 knockdown promoted cell migration, tube formation, and mitochondrial membrane potential in endothelial cells under oxidative stress. The transcriptome sequencing results unmasked mechanisms of the regulation of angiogenesis induced by SUV39H1. Finally, Salvianolic acid B and Astragaloside IV were identified as potential drug candidates for the improvement of endothelial function by repressing SUV39H1. Our study reveals a new mechanism in limb ischemia. Targeting SUV39H1 could improve endothelial dysfunction and thus prevent limb ischemia.
外周动脉疾病（PAD），其特征为外周动脉粥样硬化甚至截肢，已威胁公众的生命和健康。然而，其潜在机制在很大程度上仍不清楚。SUV39H1 是一种组蛋白甲基转移酶，可特异性地将组蛋白 H3 的赖氨酸 9 甲基化，并在转录活性中作为抑制剂。本研究旨在探讨 SUV39H1 在肢体缺血中的作用。将 C57BL/6 雄性小鼠随机分为 Sham 或 Model 组，以研究缺血肢体中 SUV39H1 的表达。然后，在肢体缺血小鼠模型中进行 SUV39H1 的药物抑制或基因缺失，以确认其对肢体缺血的作用。采用激光散斑对比成像（LSCI）定量血液灌注。通过 CD31 免疫组化染色和 HE 染色测量毛细血管密度和肌肉水肿。采用 Western blot 法确认 SUV39H1 和 Catalase 的表达。采用 siSUV39H1 对人脐静脉内皮细胞（HUVEC）的转录组测序，探讨 SUV39H1 对血管生成的调控机制。结果显示，SUV39H1 在小鼠缺血肌肉组织中高表达。药物抑制或基因缺失 SUV39H1 可显著改善缺血肌肉组织的血液灌注、毛细血管密度和血管生成。细胞实验显示，在氧化应激下，SUV39H1 敲低可促进内皮细胞的迁移、管腔形成和线粒体膜电位。转录组测序结果揭示了 SUV39H1 诱导血管生成的调节机制。最后，鉴定出丹酚酸 B 和黄芪甲苷 IV 是通过抑制 SUV39H1 改善内皮功能的潜在药物候选物。本研究揭示了肢体缺血的新机制。靶向 SUV39H1 可改善内皮功能障碍，从而预防肢体缺血。
