Cardiac hypertrophy is a common adaptive response to a variety of stimuli,but prolonged hypertrophy leads to heart failure.Hence,discovery of agents treating cardiac hypertrophy is urgently needed.In the present study,we investigated the effects of QF84139,a newly synthesized pyrazine derivative,on cardiac hypertrophy and the underlying mechanisms.In neonatal rat cardiomyocytes(NRCMs),pretreatment with QF84139(1-10 μM)concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation,increased ANP protein level and enlarged cardiomyocytes.In adult male mice,administration of QF84139(5-90 mg·kg-1·d-1,i.p.,for 2 weeks)dose-dependently reversed transverse aortic constriction(TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size,left ventricular mass,heart weights,and reactivation of fetal genes.We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKⅡδ,ERK1/2,AKT,PKCε,and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice.In NRCMs,QF84139 did not show additive effects with metformin on the AMPK activation,whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2.In AMPKα2-deficient mice,the anti-hypertrophic effect of QF84139 was also vanished.These results demonstrate that QF84139 attenuates the PE-and TAC-induced cardiac hypertrophy via activating the AMPK signaling.This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy.

Xu-xia Li;Peng Zhang;Yang Yang;Jing-jing Wang;Yan-jun Zheng;Ji-liang Tan;Shen-yan Liu;Yong-ming Yan;You-yi Zhang;Yong-xian Cheng;Huang-tian Yang

CAS Key Laboratory of Tissue Microenvironment and Tumor,Laboratory of Molecular Cardiology,Shanghai Institute of Nutrition and Health,University of Chinese Academy of Sciences,CAS,Shanghai 200031,China;State Key Laboratory of Phytochemistry and Plant Resources in West China,Kunming Institute of Botany,CAS,Kunming 650201,China;Department of Cardiology and Institute of Vascular Medicine,Peking University Third Hospital;NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides;Key Laboratory of Molecular Cardiovascular Science,Ministry of Education,Beijing Key Laboratory of Cardiovascular Receptors Research,Beijing 100191,China;School of Pharmaceutical Sciences,Health Science Center,Shenzhen University,Shenzhen 518060,China;Department of Cardiology,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai 200233,China;Institute for Stem Cell and Regeneration,CAS,Beijing 100101,China

中国药理学报（英文版）

[1]Xu-xia Li;Peng Zhang;Yang Yang;Jing-jing Wang;Yan-jun Zheng;Ji-liang Tan;Shen-yan Liu;Yong-ming Yan;You-yi Zhang;Yong-xian Cheng;Huang-tian Yang-.Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway)[J].中国药理学报（英文版）,2022(03):588-601

QF84139

Small,molecule,ameliorates,cardiac,hypertrophy,via,activating,AMPK,signaling,pathway,Cardiac,common,adaptive,variety,stimuli,but,prolonged,leads,failure,Hence,discovery,agents,treating,urgently,needed,In,present,study,investigated,effects,newly,synthesized,pyrazine,derivative,underlying,mechanisms,neonatal,cardiomyocytes,NRCMs,pretreatment,concentration,dependently,inhibited,phenylephrine,induced,hypertrophic,responses,characterized,by,fetal,genes,reactivation,increased,ANP,protein,level,enlarged,adult,male,mice,administration,weeks,dose,reversed,transverse,aortic,constriction,TAC,displayed,left,ventricular,mass,weights,We,further,revealed,that,selectively,activated,without,affecting,phosphorylation,CaMK,ERK1,AKT,PKC,P38,kinases,treated,hearts,did,not,show,additive,metformin,whereas,anti,was,abolished,inhibitor,Compound,knockdown,deficient,also,vanished,These,results,demonstrate,attenuates,PE,This,structurally,novel,compound,would,be,promising,developing,effective

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