Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure*

被引：18

作者：

Bosch, Lena ^{[1
]}

de Haan, Judith ^{[1
]}

Seijkens, Tom ^{[2
,3
]}

van Tiel, Claudia ^{[2
]}

Brans, Maike ^{[1
]}

Pasterkamp, Gerard ^{[4
]}

Lutgens, Esther ^{[2
,3
]}

de Jager, Saskia ^{[1
,5
]}

机构：

[1] Univ Med Ctr Utrecht, Expt Cardiol, Utrecht, Netherlands

[2] Acad Med Ctr Amsterdam, Dept Med Biochem, Amsterdam, Netherlands

[3] Ludwig Maximilians Univ Munchen, Inst Cardiovasc Prevent IPEK, Munich, Germany

[4] Univ Utrecht, Univ Med Ctr Utrecht, Dept Clin Chem & Haematol, Ctr Circulatory Hlth, Utrecht, Netherlands

[5] Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands

来源：

INTERNATIONAL JOURNAL OF CARDIOLOGY | 2019年 / 279卷

基金：

欧盟地平线“2020”;

关键词：

Inflammation; Heart failure; Basic science research; Animal models cardiovascular disease;

D O I：

10.1016/j.ijcard.2018.12.076

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: CD40 signalling is involved in chronic inflammation, a condition that plays an important role in nonischemic heart failure (HF). Small molecule inhibitors of CD4O-TRAF6 have shown to be effective in multiple animal models of chronic inflammatory disease, such as obesity and atherosclerosis. Methods &results: Mice were subjected lo transverse aortic constriction (TAC) and randomized to small molecule inhibition of CD4O-TRAF6 or placebo. CD40-TRAF6 inhibition resulted in less cardiac remodelling 10 weeks atter TAC with a reduced end systolic volume (TAC-placebo group: 71.9 +/- 8.8 vs TAC-CD4O-TRAF6 inhibitor: 53.7 +/- 6.1 IA, p 0.03) and improved ejection fraction (EF) compared to placebo (TAC-placebo group: 25.6 +/- 2.8 vs TAC-CD4O-TRAF6 inhibitor: 35.5 3.3%, p 0.02). Within the myocardium, CD4O-TRAF6 inhibition resulted in decreased macrophage and T-cell infiltration 10 weeks after TAC compared to placebo. In addition, a decrease in fibrosis and cardioniyocyte hypertrophy was observed in the CD4O-TRAF6 inhibitor group compared to placebo. Conclusion: CD4O-TRAF6 inhibition improves cardiac function in non-ischemic HE in mice. This effect is mediated by a reduction in macrophage and T-cell influx in the myocardium accompanied by a reduction in cardiac fibrosis and hypertrophy. (C) 2019 The Authors. Published by Elsevier B.V.

引用

页码：141 / 144

页数：4

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