Liu Jinlin, Xu Shifang, Gao Bin, Yuan Meng, Zhong Li, Guo Rui
College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding, 071002, China.
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.
Mol Cell Biochem. 2025 Jan;480(1):279-293. doi: 10.1007/s11010-024-04953-x. Epub 2024 Mar 5.
Diabetes is a major risk factor for cardiovascular disease. However, the exact mechanism by which diabetes contributes to vascular damage is not fully understood. The aim of this study was to investigate the role of SUMO-1 mediated SERCA2a SUMOylation in the development of atherosclerotic vascular injury associated with diabetes mellitus. ApoE mice were treated with streptozotocin (STZ) injection combined with high-fat feeding to simulate diabetic atherosclerosis and vascular injury. Human aortic vascular smooth muscle cells (HAVSMCs) were treated with high glucose (HG, 33.3 mM) and palmitic acid (PA, 200 µM) for 24 h to mimic a model of diabetes-induced vascular injury in vitro. Aortic vascular function, phenotypic conversion, migration, proliferation, intracellular Ca concentration, the levels of small ubiquitin-like modifier type 1 (SUMO1), SERCA2a and SUMOylated SERCA2a were detected. Diabetes-induced atherosclerotic mice presented obvious atherosclerotic plaques and vascular injury, companied by significantly lower levels of SUMO1 and SERCA2a in aorta. HG and PA treatment in HAVSMCs reduced the expressions of SUMO1, SERCA2a and SUMOylated SERCA2a, facilitated the HAVSMCs phenotypic transformation, proliferation and migration, attenuated the Ca transport, and increased the resting intracellular Ca concentration. We also confirmed that SUMO1 directly bound to SERCA2a in HAVSMCs. Overexpression of SUMO1 restored the function and phenotypic contractile ability of HAVSMCs by upregulating SERCA2a SUMOylation, thereby alleviating HG and PA-induced vascular injury. These observations suggest an essential role of SUMO1 to protect diabetes-induced atherosclerosis and aortic vascular injury by the regulation of SERCA2a-SUMOylation and calcium homeostasis.
糖尿病是心血管疾病的主要危险因素。然而，糖尿病导致血管损伤的确切机制尚未完全明确。本研究旨在探讨小泛素样修饰物1（SUMO-1）介导的肌浆网钙ATP酶2a（SERCA2a）SUMO化在糖尿病相关动脉粥样硬化血管损伤发展中的作用。通过链脲佐菌素（STZ）注射联合高脂喂养处理载脂蛋白E（ApoE）小鼠，以模拟糖尿病性动脉粥样硬化和血管损伤。用高糖（HG，33.3 mM）和棕榈酸（PA，200 µM）处理人主动脉血管平滑肌细胞（HAVSMCs）24小时，以在体外模拟糖尿病诱导的血管损伤模型。检测主动脉血管功能、表型转化、迁移、增殖、细胞内钙浓度、小泛素样修饰物1（SUMO1）、SERCA2a和SUMO化SERCA2a的水平。糖尿病诱导的动脉粥样硬化小鼠出现明显的动脉粥样硬化斑块和血管损伤，同时主动脉中SUMO1和SERCA2a水平显著降低。HG和PA处理HAVSMCs降低了SUMO1、SERCA2a和SUMO化SERCA2a的表达，促进了HAVSMCs的表型转化、增殖和迁移，减弱了钙转运，并增加了静息细胞内钙浓度。我们还证实SUMO1在HAVSMCs中直接与SERCA2a结合。SUMO1的过表达通过上调SERCA2a SUMO化恢复了HAVSMCs的功能和表型收缩能力，从而减轻了HG和PA诱导的血管损伤。这些观察结果表明SUMO1通过调节SERCA2a-SUMO化和钙稳态在保护糖尿病诱导的动脉粥样硬化和主动脉血管损伤中起重要作用。
