Gao Jian-Jun, Wu Fang-Yuan, Liu Yu-Jia, Li Le, Lin Yi-Jun, Kang Yue-Ting, Peng Yue-Ming, Liu Yi-Fang, Wang Chen, Ma Zhen-Sheng, Cao Yang, Cao Hong-Yu, Mo Zhi-Wei, Li Yan, Ou Jing-Song, Ou Zhi-Jun
Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, NHC key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University), Key Laboratory of Assisted Circulation and Vascular Diseases, Chinese Academy of Medical Sciences, Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China.
Sci China Life Sci. 2024 Dec;67(12):2635-2649. doi: 10.1007/s11427-023-2688-8. Epub 2024 Aug 15.
Diabetic foot ulcers (DFUs) are a serious vascular disease. Currently, no effective methods are available for treating DFUs. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid levels to promote atherosclerosis. However, the role of PCSK9 in DFUs remains unclear. In this study, we found that the expression of PCSK9 in endothelial cells (ECs) increased significantly under high glucose (HG) stimulation and in diabetic plasma and vessels. Specifically, PCSK9 promotes the E3 ubiquitin-protein ligase NEDD4 binding to vascular endothelial growth factor receptor 2 (VEGFR2), which led to the ubiquitination of VEGFR2, resulting in its degradation and downregulation in ECs. Furthermore, PCSK9 suppresses the expression and activation of AKT, endothelial nitric oxide synthase (eNOS), and ERK1/2, leading to decreased nitric oxide (NO) production and increased superoxide anion (O) generation, which impairs vascular endothelial function and angiogenesis. Importantly, using evolocumab to limit the increase in PCSK9 expression blocked the HG-induced inhibition of NO production and the increase in O production, as well as inhibited the phosphorylation and expression of AKT, eNOS, and ERK1/2. Moreover, evolocumab improved vascular endothelial function and angiogenesis, and promoted wound healing in diabetes. Our findings suggest that targeting PCSK9 is a novel therapeutic approach for treating DFUs.
糖尿病足溃疡（DFUs）是一种严重的血管疾病。目前，尚无有效的方法可用于治疗DFUs。前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）调节血脂水平以促进动脉粥样硬化。然而，PCSK9在DFUs中的作用仍不清楚。在本研究中，我们发现，在高糖（HG）刺激下以及在糖尿病患者的血浆和血管中，内皮细胞（ECs）中PCSK9的表达显著增加。具体而言，PCSK9促进E3泛素蛋白连接酶NEDD4与血管内皮生长因子受体2（VEGFR2）结合，导致VEGFR2泛素化，从而使其在ECs中降解并下调。此外，PCSK9抑制AKT、内皮型一氧化氮合酶（eNOS）和ERK1/2的表达和激活，导致一氧化氮（NO）生成减少和超氧阴离子（O）生成增加，从而损害血管内皮功能和血管生成。重要的是，使用依洛尤单抗限制PCSK9表达的增加可阻断HG诱导的NO生成抑制和O生成增加，并抑制AKT、eNOS和ERK1/2的磷酸化和表达。此外，依洛尤单抗改善了血管内皮功能和血管生成，并促进了糖尿病患者的伤口愈合。我们的研究结果表明，靶向PCSK9是一种治疗DFUs的新型治疗方法。
