Qian Zonghao, Huang Yuzhen, Yang Ni, Fang Ziwei, Zhang Yucong, Huang Yi, Luo Mandi, Ji Tianyi, Chen Zuoguan, Gao Shang, Li Yongjun, Yan Jinhua, Jiang Dingsheng, Ruan Lei, Liu Anding, Zhang Cuntai, Zhang Le
Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.
Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Beijing 100730, China.
Mech Ageing Dev. 2025 Jun;225:112060. doi: 10.1016/j.mad.2025.112060. Epub 2025 Apr 11.
Vascular aging is a key driver of age-related cardiovascular and metabolic diseases, with endothelial dysfunction and senescence as a central mechanism. In our recent study, we observed elevated ADAM10 protein levels in senescent endothelial cells, which worsened endothelial dysfunction and senescence. However, the regulatory mechanisms controlling ADAM10 expression are poorly understood. In this study, we show that ADAM10 undergoes post-transcriptional modification in senescent human umbilical vein endothelial cells (HUVECs), with the E3 ubiquitin ligase MARCHF8 predicted to facilitate its ubiquitination-dependent degradation. We also found that MARCHF8 expression was significantly reduced in senescent HUVECs. Knockdown of MARCHF8 in young HUVECs induced endothelial senescence and impaired key endothelial functions, including migration, proliferation, angiogenesis, and nitric oxide production. Conversely, overexpression of MARCHF8 in senescent HUVECs ameliorated senescence-associated dysfunctions. RNA sequencing analysis revealed that MARCHF8 knockdown disrupted pathways linked to cell senescence and atherosclerosis. In vivo, MARCHF8 overexpression in high-fat diet-fed apoE mice reduced plasma interleukin-6 levels and attenuated atherosclerosis progression. Additionally, miR-34a-5p upregulation in senescence inhibited MARCHF8 expression, compromising its protective effects in delaying endothelial senescence. Collectively, these findings reveal a novel miR-34a-5p/MARCHF8/ADAM10 axis in vascular endothelial senescence, positioning MARCHF8 as a potential biomarker and therapeutic target for vascular aging and related diseases.
血管老化是与年龄相关的心血管和代谢疾病的关键驱动因素，其中心机制是内皮功能障碍和衰老。在我们最近的研究中，我们观察到衰老内皮细胞中ADAM10蛋白水平升高，这加剧了内皮功能障碍和衰老。然而，控制ADAM10表达的调节机制尚不清楚。在本研究中，我们表明ADAM10在衰老的人脐静脉内皮细胞（HUVECs）中经历转录后修饰，预测E3泛素连接酶MARCHF8促进其泛素化依赖性降解。我们还发现衰老的HUVECs中MARCHF8表达显著降低。在年轻的HUVECs中敲低MARCHF8会诱导内皮衰老并损害关键的内皮功能，包括迁移、增殖、血管生成和一氧化氮产生。相反，在衰老的HUVECs中过表达MARCHF8可改善衰老相关功能障碍。RNA测序分析表明，敲低MARCHF8会破坏与细胞衰老和动脉粥样硬化相关的途径。在体内，在高脂饮食喂养的载脂蛋白E小鼠中过表达MARCHF8可降低血浆白细胞介素-6水平并减缓动脉粥样硬化进展。此外，衰老过程中miR-34a-5p上调抑制MARCHF8表达，损害其在延缓内皮衰老中的保护作用。总的来说，这些发现揭示了血管内皮衰老中一种新的miR-34a-5p/MARCHF8/ADAM10轴，将MARCHF8定位为血管老化及相关疾病的潜在生物标志物和治疗靶点。
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