Reversing metabolic reprogramming by CPT1 inhibition with etomoxir promotes cardiomyocyte proliferation and heart regeneration via DUSP1 ADP-ribosylationmediated p38 MAPK phosphorylation  

作　　者：Luxun Tang Yu Shi Qiao Liao Feng Wang Hao Wu Hongmei Ren Xuemei Wang Wenbin Fu Jialing Shou Wei Eric Wang Pedro AJose Yongjian Yang Chunyu Zeng 

机构地区：[1]Department of Cardiology,Daping Hospital,the Third Military Medical University(Army Medical University),Chongqing 400042,China [2]Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research,Ministry of Education of China,Chongqing Key Laboratory for Hypertension Research,Chongqing Cardiovascular Clinical Research Center,Chongqing Institute of Cardiology,Chongqing 400042,China [3]Department of Cardiovascular Medicine,the General Hospital of Western Theater Command,Chengdu 610083,China [4]Division of Renal Diseases and Hypertension,the George Washington University School of Medicine and Health Sciences,Washington,DC 20541,USA [5]State Key Laboratory of Trauma,Burns and Combined Injury,Daping Hospital,the Third Military Medical University,Chongqing 400042,China [6]Cardiovascular Research Center of Chongqing College,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Chongqing 400042,China [7]Department of Cardiology,the First Affiliated Hospital of Kunming Medical University,Kunming 650000,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第1期256-277,共22页药学学报(英文版)

基　　金：supported by grants from the National Key Research and Development Program of China(No.2022YFA1104500);National Natural Science Foundation of China(No.81930008);Natural Science Foundation of Sichuan Province(No.2023NSFSC1651,China);the National Institutes of Health(No.DK134574 and No.DK119652,US).

摘　　要：The neonatal mammalian heart has a remarkable regenerative capacity,while the adult heart has difficulty to regenerate.A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of cardiomyocyte proliferative capacity shortly after birth.In this study,we sought to determine if and how metabolic reprogramming regulates cardiomyocyte proliferation.Reversing metabolic reprogramming by carnitine palmitoyltransferase 1(CPT1)inhibition,using cardiac-specific Cpt1a and Cpt1b knockout mice promoted cardiomyocyte proliferation and improved cardiac function post-myocardial infarction.The inhibition of CPT1 is of pharmacological significance because those protective effects were replicated by etomoxir,a CPT1 inhibitor.CPT1 inhibition,by decreasing poly(ADP-ribose)polymerase 1 expression,reduced ADP-ribosylation of dual-specificity phosphatase 1 in cardiomyocytes,leading to decreased p38 MAPK phosphorylation,and stimulation of cardiomyocyte proliferation.Our present study indicates that reversing metabolic reprogramming is an effective strategy to stimulate adult cardiomyocyte proliferation.CPT1 is a potential therapeutic target for promoting heart regeneration and myocardial infarction treatment.

关 键 词：Metabolic reprogramming Cardiomyocyte proliferation Carnitine palmitoyltransferase l ETOMOXIR Fatty acid oxidation GLYCOLYSIS ADP-RIBOSYLATION p38MAPK 

分 类 号：R73[医药卫生—肿瘤]