SGLT2 inhibitor empagliflozin alleviates cardiac remodeling and contractile anomalies in a FUNDC1-dependent manner in experimental Parkinson's disease  

作　　者：Wei Yu Lin Wang Wei-ying Ren Hai-xia Xu Ne N.Wu Dong-hui Yu Russel J.Reiter Wen-liang Zha Qing-dong Guo Jun Ren 

机构地区：[1]Xinning Medical College,Hubei University of Science and Technology,Xianning 437100,China [2]Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province,Xianning 437100,China [3]Department of Geriatrics,Xijing Hospital,the Air Force Military Medical University,Xi'an 710032,China [4]Department of Geriatrics,Zhongshan Hospital Fudan University,Shanghai 200032,China [5]SDepartment of Cardiology,Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital,Fudan University,Shanghai 200032,China [6]National Clinical Research Center for Interventional Medicine,Shanghai 200032,China [7]Department of Cardiology,Afliated Hospital of Nantong Universit,Nantong 226001,China [8]Xianning Central Hospital,Xianning 437100,China [9]Department of Cell Systems and Anatomy,UT Health San Antonio,San Antonio,TX,USA [10]Second Affliated Hospital,Xianning Medical College,Hubei University of Science and Technology,Xianning 437100,China [11]Department of Neurosurgery,Xijing Hospital,Air Force Medical University,Xi'an 710032,China

出　　处：《Acta Pharmacologica Sinica》2024年第1期87-97,共11页中国药理学报（英文版）

基　　金：supported in part by the National Natural Science Foundation of China(92249301);Fund Project of Hubei University of Science and Technology(2022YKY06);the Hubei Province Research Innovation Team Project(T2021022);Scientific Research Projects of Hubei Health Commission(WJ2023M119).

摘　　要：Recent evidence shows a close link between Parkinson's disease(PD)and cardiac dysfunction with limited treatment options.Mitophagy plays a crucial role in the control of mitochondrial quantity,metabolic reprogramming and cell differentiation.Mutation of the mitophagy protein Parkin is directly associated with the onset of PD.Parkin-independent receptor-mediated mitophagy is also documented such as BCL2/adenovirus E1B 19 kDa protein-interacting protein 3(BNIP3)and FUN14 domain containing 1(FUNDC1)for receptor-mediated mitophagy.In this study we investigated cardiac function and mitophagy including FUNDC1 in PD patients and mouse models,and evaluated the therapeutic potential of a SGLT2 inhibitor empagliflozin.MPTP-induced PD model Was established.PD patients and MPTP mice not only displayed pronounced motor defects,but also low plasma FUNDC1 levels,as well as cardiac ultrastructural and geometric anomalies(cardiac atrophy,interstitial fibrosis),functional anomalies(reduced E/A ratio,fractional shortening,ejection fraction,cardiomyocyte contraction)and mitochondrial injury(ultrastructural damage,UcP2,PGC1a,elevated mitochondrial Ca2+uptake proteins MCU and VDAC1,and mitochondrial apoptotic protein calpain),dampened autophagy,FUNDC1 mitophagy and apoptosis.By Gene set enrichment analysis(GSEA),we found overtly altered glucose transmembrane transport in the midbrains of MPTP-treated mice.Intriguingly,administration of SGLT2 inhibitor empagliflozin(10 mg/kg,ip,twice per week for 2 weeks)in MPTP-treated mice significantly ameliorated myocardial anomalies(with exception of VDAC1),but did not reconcile the motor defects or plasma FUNDCi.FUNDC1 global knockout(FUNDC1-/-mice)did not elicit any phenotype on cardiac geometry or function in the absence or presence of MPTP insult,but it nullified empagliflozin-caused cardioprotection against MPTP-induced cardiac anomalies including remodeling(atrophy and fibrosis),contractile dysfunction,Ca2+homeostasis,mitochondrial(including MCU,mitochondrial Ca2+overload,calpain,PARP1)and a

关 键 词：Parkinson's disease cardiac dysfunction FUNDC1 MITOCHONDRIA MCU empagliflozin 

分 类 号：R742.5[医药卫生—神经病学与精神病学]