Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway  

作　　者：Xia-yun Ni Xiao-jun Feng Zhi-hua Wang Yang Zhang Peter J.Little Yang Cao Suo-wen Xu Li-qin Tang Jian-ping Weng 

机构地区：[1]Department of Endocrinology,Institute of Endocrine and Metabolic Disease,The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,Clinical Research Hospital of Chinese Academy of Sciences(Hefei),University of Science and Technology of China,Hefei,230036,China [2]Department of Pharmacy,The First Affiliated Hospital of University of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China(USTC),Hefei,230001,China [3]School of Pharmacy,University of Queensland,Pharmacy Australia Centre of Excellence,Woolloongabba,QLD,4102,Australia [4]Division of Life Sciences and Medicine,University of Science and Technology of China(USTC),Hefei,230022,China

出　　处：《Acta Pharmacologica Sinica》2024年第8期1604-1617,共14页中国药理学报（英文版）

基　　金：supported by grants from the National Key R&D Program of China(Grant No.2021YFC2500500);National Natural Science Foundation of China(No.82003740,No.82174031,No.82070464,No.82370444,No.82102804);the Doctoral Research Fund(RC2021015);the China Postdoctoral Science Foundation(No.2021M693102);Scientific Research Project of Anhui Provincial Education Department(2022AH040184);supported by the Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG02);Anhui Provincial Key Research and Development Program(Grant No.202104j07020051);Anhui Provincial Natural Science Foundation(Grant No.2208085J08).

摘　　要：Heart failure with preserved ejection fraction(HFpEF)is closely associated with metabolic derangement.Sodium glucose cotransporter-2 inhibitors(SGLT2i)and glucagon-like peptide-1 receptor agonists(GLP-1RA)exert anti-HFpEF effects,but the underlying mechanisms remain unclear.In this study,we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF.This model was established by high-fat diet(HFD)feeding plus Nω-nitro-L-arginine methyl ester(L-NAME)treatment.The mice were treated with empagliflozin(20 mg·kg^(-1)·d^(-1),i.g.)or liraglutide(0.3 mg·kg^(-1)·d^(-1),i.p.)or their combination for 4 weeks.At the end of the experimental protocol,cardiac function was measured using ultrasound,then mice were euthanized and heart,liver,and kidney tissues were collected.Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing(snRNA-seq).We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function,ameliorated cardiomyocyte hypertrophy and cardiac fibrosis,as well as exercise tolerance but no synergism was observed in the combination group.Furthermore,empagliflozin and/or liraglutide lowered body weight,improved glucose metabolism,lowered blood pressure,and improved liver and kidney function.After the withdrawal of empagliflozin or liraglutide for 1 week,these beneficial effects tended to diminish.The snRNA-seq analysis revealed a subcluster of myocytes,in which Erbb4 expression was down-regulated under HFpEF conditions,and restored by empagliflozin or liraglutide.Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions.In the HFpEF mouse model,both empagliflozin and liraglutide reversed Erbb4 down-regulation.In rat h9c2 cells,we showed that palmitic acid-or high glucose-induced changes in PKCαand/or ERK1/2 phosphorylation at least in part through Erb

关 键 词：HFpEF empagliflozin LIRAGLUTIDE ERBB4 snRNA-seq 

分 类 号：R285[医药卫生—中药学]