首页|Increase of PCSK9 expression in diabetes promotes VEGFR2 ubiquitination to inhibit endothelial function and skin wound healing

Increase of PCSK9 expression in diabetes promotes VEGFR2 ubiquitination to inhibit endothelial function and skin wound healing

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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(O2·-)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 O2·- 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.

Diabetic foot ulcersPCSK9endothelial functionangiogenesisVEGFR2

Jian-Jun Gao、Fang-Yuan Wu、Yu-Jia Liu、Le Li、Yi-Jun Lin、Yue-Ting Kang、Yue-Ming Peng、Yi-Fang Liu、Chen Wang、Zhen-Sheng Ma、Yang Cao、Hong-Yu Cao、Zhi-Wei Mo、Yan Li、Jing-Song Ou、Zhi-Jun Ou

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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 Vascu

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

Division of Hypertension and Vascular Diseases,Department of Cardiology,Heart Center,The First Affilia

Division of Vascular Surgery,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,Chi

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2024

10.1007/s11427-023-2688-8

中国科学:生命科学(英文版)
中国科学院

中国科学:生命科学(英文版)

CSTPCD
影响因子：0.806
ISSN：1674-7305
年,卷(期)：2024.67(12)