Antibody-mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload

被引：11

作者：

Lim, Wei-Wen ^{[1
,2
]}

Corden, Ben ^{[1
,2
,3
,4
]}

Ye, Lei ^{[1
]}

Viswanathan, Sivakumar ^{[2
]}

Widjaja, Anissa A. ^{[2
]}

Xie, Chen ^{[1
]}

Su, Liping ^{[1
]}

Tee, Nicole G. Z. ^{[1
]}

Schafer, Sebastian ^{[1
,2
]}

Cook, Stuart A. ^{[1
,2
,3
,4
]}

机构：

[1] Natl Heart Ctr Singapore, Natl Heart Res Inst Singapore, 5 Hosp Dr, Singapore 169609, Singapore

[2] Duke Natl Univ, Cardiovasc & Metab Disorders Program, Singapore Med Sch, Singapore, Singapore

[3] Hammersmith Hosp Campus, London Inst Med Sci, MRC, London, England

[4] Imperial Coll London, Natl Heart & Lung Inst, London, England

来源：

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY | 2021年 / 48卷 / 04期

基金：

英国医学研究理事会;

关键词：

antibodies; aortic stenosis; cardiac fibrosis; cardiac hypertrophy; heart failure; interleukin-11; TRANSVERSE AORTIC CONSTRICTION; HYPERTROPHY; MICE; HYPERTENSION; PREVENTS;

D O I：

10.1111/1440-1681.13458

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Interleukin-11 (IL11) is important for fibroblast-to-myofibroblast transformations. Here, we examined the signalling and phenotypic effects of inhibiting IL11 signalling using neutralizing antibodies against IL11 or its cognate receptor (IL11RA) in a mouse model of acute and severe pressure overload. C57BL/6J mice underwent ascending aortic constriction (AAC) surgery and were randomized to anti-IL11, anti-IL11RA, or isotype control antibodies (20 mg/kg, bi-weekly for 2 weeks). AAC surgery induced the expression of IL11, IL11RA and extracellular matrix (ECM) genes that was associated with cardiac hypertrophy and aortic remodelling. Inhibition of IL11 signalling reduced AAC-induced cardiac fibrosis and ECM gene expression as well as ERK1/2 phosphorylation but had no effect on cardiac hypertrophy. STAT3 was phosphorylated in the hearts of AAC-treated mice but this was unrelated to IL11 activity, which we confirmed in mouse cardiac fibroblasts in vitro. These data highlight that blocking IL11 signalling reduces cardiac fibrosis due to severe pressure overload and suggests ERK, but not STAT3, activity as the relevant underlying signalling pathway.

引用

页码：605 / 613

页数：9

共 39 条

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