Myocyte enhancer factor 2A orchestrates vascular redox homeostasis via direct transcriptional activation of SIRT1OA
Myocyte enhancer factor 2A(MEF2A),a transcription factor implicated in coronary artery disease,remains unexplored in vascular redox regulation.To address this gap and overcome the limitations of current antioxidant therapies,we investigate the role of MEF2A in oxidative defense via human umbilical vein endothelial cells(HUVECs)and murine models.Adenoviral vectors encoding MEF2A‑specific shRNAs or mRNAs are used to silence or overexpress MEF2A in HUVECs.For in vivo validation,endothelial‑targeted MEF2A knockdown is achieved via AAV1‑shRNA delivery in mice fed with a high‑fat diet.Systemic redox status is assessed by measuring reactive oxygen species(ROS),glutathione homeostasis(GSH/GSSG ratio),the NADH/NAD+balance,the mitochondrial membrane potential(ΔΨm),and 8‑hydroxy‑2''‑deoxyguanosine(8‑OHdG).Mechanistic insights are derived from immunofluorescence,qPCR,western blotting,and dual‑luciferase reporter assays.MEF2A silencing induces redox imbalance,characterized by elevated ROS,a reduced GSH/GSSG ratio,andΔΨm collapse.Conversely,MEF2A overexpression synergizes with SIRT1 to restore the glutathione pool,maintain NAD+homeostasis,and suppress ROS under oxidative stress.Chromatin immunoprecipitation confirms that MEF2A directly binds to two cis‑elements in the SIRT1 promoter,driving transcriptional activation.In vivo,MEF2A‑deficient mice present increased vascular oxidative damage,as indicated by elevated DNA damage marker(8‑OHdG)and ROS levels.The down‑regulation of SIRT1/PGC‑1αin MEF2A‑silenced cells is verified in vivo.Our findings establish MEF2A as a master regulator of endothelial redox defense via the SIRT1‑PGC‑1αaxis,providing a mechanistic foundation for the treatment of oxidative cardiovascular disorders.This work suggests that pharmacological MEF2A activation is a novel strategy for precision antioxidant therapy in vascular medicine.
Benrong Liu;Lei Fang;Chunxia Miao;Xinyu Wen;Xiumiao Zheng;Minxing Xu;Junli Lin;Yujuan Xiong;Shi-Ming Liu
Department of Cardiology,Guangzhou Institute of Cardiovascular Disease,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Disease,the Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510260,ChinaDepartment of Cardiology,Guangzhou Institute of Cardiovascular Disease,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Disease,the Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510260,ChinaDepartment of Cardiology,Guangzhou Institute of Cardiovascular Disease,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Disease,the Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510260,ChinaDepartment of Cardiology,Guangzhou Institute of Cardiovascular Disease,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Disease,the Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510260,ChinaDepartment of Cardiology,Guangzhou Institute of Cardiovascular Disease,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Disease,the Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510260,ChinaDepartment of Cardiology,Guangzhou Institute of Cardiovascular Disease,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Disease,the Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510260,ChinaDepartment of Cardiology,Guangzhou Institute of Cardiovascular Disease,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Disease,the Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510260,ChinaDepartment of Laboratory Medicine,Panyu Hospital,Guangzhou University of Chinese Medicine,Guangzhou 511400,ChinaDepartment of Cardiology,Guangzhou Institute of Cardiovascular Disease,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Disease,the Second Affiliated Hospital,Guangzhou Medical University,Guangzhou 510260,China
医药卫生
oxidative stressMEF2Aredox homeostasisGSH/GSSG ratiocardiovascular diseaseNADH/NAD+ratio
《Acta Biochimica et Biophysica Sinica》 2026 (5)
P.1069-1082,14
supported by the grants from the Guangzhou Municipal Science and Technology Project(No.2024A03J0940 to B.L.)the Graduate Research Project of the Guangzhou Education Bureau(No.2024312106 to B.L.)the Key Medical Disciplines and Specialties Program of Guangzhou(No.2025‑2027 to S.M.L.)the Innovation Team of General Universities in Guangdong Province(No.2023KCXTD025 to S.M.L.).
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