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Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes after myocardial infarction
Alison K. Schroer, … , Hind Lal, W. David Merryman
Alison K. Schroer, … , Hind Lal, W. David Merryman
Published September 19, 2019
Citation Information: JCI Insight. 2019;4(18):e131545. https://doi.org/10.1172/jci.insight.131545.
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Research Article Cardiology

Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes after myocardial infarction

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Abstract

Over one million Americans experience myocardial infarction (MI) annually, and the resulting scar and subsequent cardiac fibrosis gives rise to heart failure. A specialized cell-cell adhesion protein, cadherin-11 (CDH11), contributes to inflammation and fibrosis in rheumatoid arthritis, pulmonary fibrosis, and aortic valve calcification but has not been studied in myocardium after MI. MI was induced by ligation of the left anterior descending artery in mice with either heterozygous or homozygous knockout of CDH11, wild-type mice receiving bone marrow transplants from Cdh11-deficient animals, and wild-type mice treated with a functional blocking antibody against CDH11 (SYN0012). Flow cytometry revealed significant CDH11 expression in noncardiomyocyte cells after MI. Animals given SYN0012 had improved cardiac function, as measured by echocardiogram, reduced tissue remodeling, and altered transcription of inflammatory and proangiogenic genes. Targeting CDH11 reduced bone marrow–derived myeloid cells and increased proangiogenic cells in the heart 3 days after MI. Cardiac fibroblast and macrophage interactions increased IL-6 secretion in vitro. Our findings suggest that CDH11-expressing cells contribute to inflammation-driven fibrotic remodeling after MI and that targeting CDH11 with a blocking antibody improves outcomes by altering recruitment of bone marrow–derived cells, limiting the macrophage-induced expression of IL-6 by fibroblasts and promoting vascularization.

Authors

Alison K. Schroer, Matthew R. Bersi, Cynthia R. Clark, Qinkun Zhang, Lehanna H. Sanders, Antonis K. Hatzopoulos, Thomas L. Force, Susan M. Majka, Hind Lal, W. David Merryman

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Figure 3

CDH11 blockade improves functional outcomes after MI.

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CDH11 blockade improves functional outcomes after MI.
Echocardiographic ...
Echocardiographic analysis of infarcted hearts revealed that ejection fraction (A), left ventricular (LV) mass (B), and LV volume (C and D) was significantly changed from baseline in all groups. SYN0012-treated hearts had significantly higher ejection fraction at 7 and 21 days after infarct, and reduced LV volume at 21 and 56 days after infarct, compared with IgG2a-treated controls; LV mass was not different between treatments at any time point. Data are presented as mean ± SEM. Significance was determined by mixed-effect analysis with a Holms-Sidak’s multiple comparison test. *P < 0.05 between treatments, ^P < 0.05 between time points; color of significance marker denotes treatment group.

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