Gefapixant,a Novel P2X3 Antagonist,Protects against Post Myocardial Infarction Cardiac Dysfunction and Remodeling Via Suppressing NLRP3 Inflammasome  

作　　者：Yan-zhao WEI Shuang YANG Wei LI Yan-hong TANG 

机构地区：[1]Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,430060,China [2]Cardiovascular Research Institute,Wuhan University,Wuhan,430060,China [3]Hubei Key Laboratory of Cardiology,Wuhan,430060,China [4]Department of Cardiology,Wuhan No.1 Hospital,Wuhan Hospital of Traditional Chinese and Western Medicine,Wuhan,430022,China

出　　处：《Current Medical Science》2023年第1期58-68,共11页当代医学科学（英文）

基　　金：supported by the National Natural Science Foundation of China(No.81370282).

摘　　要：Objective The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family.Among these,P2X3 is a type of P2X receptor which is specifically expressed on nerves,especially on pre-ganglionic sensory fibers.This study investigates whether gefapixant possesses the potential of inhibiting cardiac sympathetic hypersensitivity to protect against cardiac remodeling in the context of myocardial infarction.Methods The Sprague-Dawley rats were divided randomly into three groups:sham group-myocardial infarction group,and myocardial infarction with gefapixant treatment group.Myocardial infarction was induced by left anterior descending branch ligation.The gefapixant solution was intraperitoneally injected each time per day for 7 days and the appropriate dosage of gefapixant was determined according to the results of hematoxylin-eosin(HE)staining and myocardial injury biomarkers.Conditions of cardiac function were assessed by echocardiograph and cardiac fibrosis was evaluated by Western blotting and immunofluorescence staining of collagen I and collagen III.The sympathetic innervation was detected by norepinephrine concentration(pg/mL),in-vivo electrophysiology,and typical sympathetic biomarkers.Inflammatory cell infiltration was shown from immunofluorescence staining and pro-inflammatory signaling pathway activation was checked by immunohistology,quantitative realtime PCR(qPCR)and Western blotting.Results It was found that gefapixant injection of 10 mg/kg per day had the highest dosage-efficacy ratio.Furthermore,gefapixant treatment improved cardiac pump function as shown by increased LVEF and LVFS,and decreased LVIDd and LVIDs.The expression levels of collagen I and collagen III,and TNF-αwere all decreased by P2X3 inhibition.Mechanistically,the decreased activation of nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3(NLRP3)inflammasome and subsequent cleavage of caspase-1 which modulated interleukin-1β(IL-1β)and IL-18 level in h

关 键 词：myocardial infarction P2X3 inhibition gefapixant nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3 INFLAMMASOME sympathetic nerve 

分 类 号：R542.22[医药卫生—心血管疾病]