Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice

被引：116

作者：

Qin, Cheng Xue ^{[1
,2
]}

May, Lauren T. ^{[3
]}

Li, Renming ^{[1
,2
]}

Cao, Nga ^{[1
]}

Rosli, Sarah ^{[1
]}

Minh Deo ^{[1
]}

Alexander, Amy E. ^{[1
]}

Horlock, Duncan ^{[1
]}

Bourke, Jane E. ^{[4
]}

Yang, Yuan H. ^{[5
]}

Stewart, Alastair G. ^{[2
]}

Kaye, David M. ^{[1
]}

Du, Xiao-Jun ^{[1
]}

Sexton, Patrick M. ^{[3
]}

Christopoulos, Arthur ^{[3
]}

Gao, Xiao-Ming ^{[1
]}

Ritchie, Rebecca H. ^{[1
,2
,6
]}

机构：

[1] Baker IDI Heart & Diabet Inst, 75 Commercial Rd, Melbourne, Vic 3004, Australia

[2] Univ Melbourne, Dept Pharmacol, Melbourne, Vic 3010, Australia

[3] Monash Univ, Dept Pharmacol, Div Drug Discovery Biol, 381 Royal Parade, Parkville, Vic 3052, Australia

[4] Monash Univ, Dept Pharmacol, Wellington Rd & Blackburn Rd, Clayton, Vic 3800, Australia

[5] Monash Univ, Ctr Inflammatory Dis, Clayton, Vic 3168, Australia

[6] Monash Univ, Dept Med, Parkville, Vic 3800, Australia

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

英国医学研究理事会;

关键词：

RAT CARDIOMYOCYTES; SIMULATED ISCHEMIA; LIGAND; HEART; DYSFUNCTION; EXPRESSION; INFARCTION; ANNEXIN-A1; RESOLUTION; MODEL;

D O I：

10.1038/ncomms14232

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Effective treatment for managing myocardial infarction (MI) remains an urgent, unmet clinical need. Formyl peptide receptors (FPR) regulate inflammation, a major contributing mechanism to cardiac injury following MI. Here we demonstrate that FPR1/FPR2-biased agonism may represent a novel therapeutic strategy for the treatment of MI. The small-molecule FPR1/FPR2 agonist, Compound 17b (Cmpd17b), exhibits a distinct signalling fingerprint to the conventional FPR1/FPR2 agonist, Compound-43 (Cmpd43). In Chinese hamster ovary (CHO) cells stably transfected with human FPR1 or FPR2, Compd17b is biased away from potentially detrimental FPR1/2-mediated calcium mobilization, but retains the pro-survival signalling, ERK1/2 and Akt phosphorylation, relative to Compd43. The pathological importance of the biased agonism of Cmpd17b is demonstrable as superior cardioprotection in both in vitro (cardiomyocytes and cardiofibroblasts) and MI injury in mice in vivo. These findings reveal new insights for development of small molecule FPR agonists with an improved cardioprotective profile for treating MI.

引用

页数：13

共 14 条

[11] Erythropoietin enhances cardiac contractility, endothelin and B-type natriuretic peptide secretion and protects heart against ischaemia-reperfusion injury
Piuhola, J.
Pemberton, C. J.
Keenan, J. I.
Kerkelä, R.
Hampton, M. B.
Richards, A. M.
EUROPEAN HEART JOURNAL, 2005, 26 : 10 - 10
[12] B7-33,a Functionally Selective Relaxin Receptor 1 Agonist, Exerts Protective Effects Against Myocardial ischemia-Reperfusion Injury in Mice
Devarakonda, Teja
Mauro, Adolfo G.
Guzman, Geronimo
Cain, Chad
Das, Anindita
Praveen, Praveen
Hossain, M. A.
Salloum, Fadi N.
CIRCULATION RESEARCH, 2019, 125
[13] Salvianolic acid B protects against myocardial ischaemia-reperfusion injury in rats via inhibiting high mobility group box 1 protein expression through the PI3K/Akt signalling pathway
Hanqing Liu
Wei Liu
Huiliang Qiu
Dezhi Zou
Huayang Cai
Qiuxiong Chen
Chaoyang Zheng
Danping Xu
Naunyn-Schmiedeberg's Archives of Pharmacology, 2020, 393 : 1527 - 1539
[14] Salvianolic acid B protects against myocardial ischaemia-reperfusion injury in rats via inhibiting high mobility group box 1 protein expression through the PI3K/Akt signalling pathway
Liu, Hanqing
Liu, Wei
Qiu, Huiliang
Zou, Dezhi
Cai, Huayang
Chen, Qiuxiong
Zheng, Chaoyang
Xu, Danping
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2020, 393 (08) : 1527 - 1539

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