IMM-H007 attenuates isoprenaline-induced cardiac fibrosis through targeting TGFβ1 signaling pathway  

作　　者：Shuai-xing Wang Ye-nan Feng Shan Feng Ji-min Wu Mi Zhang Wen-li Xu You-yi Zhang Hai-bo Zhu Han Xiao Er-dan Dong 

机构地区：[1]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 [2]State Key Laboratory for Bioactive Substances and Functions of Natural Medicines,Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China

出　　处：《Acta Pharmacologica Sinica》2022年第10期2542-2549,共8页中国药理学报（英文版）

基　　金：This work was supported by the National Key R&D Program(grant numbers 2020YFC2004704 to HX);Natural Science Foundation of China(grant numbers 82030072 to HX,81830009 to YYZ,and 82070235 to EDD);the Beijing Municipal Natural Science Foundation(grant number 7191013 to EDD);Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases,Chinese Academy of Medical Sciences(2021RU003 to EDD);the Key Clinical Projects of Peking University Third Hospital[BYSYZD2019022 to HX].

摘　　要：Upon chronic stress,β-adrenergic receptor activation induces cardiac fibrosis and leads to heart failure.The small molecule compound IMM-H007 has demonstrated protective effects in cardiovascular diseases via activation of AMP-activated protein kinase(AMPK).This study aimed to investigate IMM-H007 effects on cardiac fibrosis induced byβ-adrenergic receptor activation.Because adenosine analogs also exert AMPK-independent effects,we assessed AMPK-dependent and-independent IMM-H007 effects in murine models of cardiac fibrosis.Continual subcutaneous injection of isoprenaline for 7 days caused cardiac fibrosis and cardiac dysfunction in mice in vivo.IMM-H007 attenuated isoprenaline-induced cardiac fibrosis,diastolic dysfunction,α-smooth muscle actin expression,and collagen I deposition in both wild-type and AMPKα2^(-/-)mice.Moreover,IMM-H007 inhibited transforming growth factorβ1(TGFβ1)expression in wild-type,but not AMPKα2^(-/-)mice.By contrast,IMM-H007 inhibited Smad2/3 signaling downstream of TGFβ1 in both wild-type and AMPKα2^(-/-)mice.Surface plasmon resonance and molecular docking experiments showed that IMM-H007 directly interacts with TGFβ1,inhibits its binding to TGFβtype II receptors,and downregulates the Smad2/3 signaling pathway downstream of TGFβ1.These findings suggest that IMM-H007 inhibits isoprenaline-induced cardiac fibrosis via both AMPKα2-dependent and-independent mechanisms.IMM-H007 may be useful as a novel TGFβ1 antagonist.

关 键 词：IMM-H007 sympathetic stress cardiac fibrosis AMP-activated protein kinase transforming growth factorβ1 

分 类 号：R965[医药卫生—药理学]