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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 4

CDH11 blockade limits fibrotic remodeling after MI.

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CDH11 blockade limits fibrotic remodeling after MI.
Atomic force microsc...
Atomic force microscopy was used to quantify local tissue stiffness, as shown by representative stiffness color maps (A). Calculation of median stiffness values from each scan revealed a decrease at 7 days after MI, with all of the IgG2a hearts falling outside the range of the sham myocardium. Median stiffness values increased by 21 days and remained elevated out to 56 days in IgG2a-treated hearts, whereas SYN0012-treated hearts increased to a lesser extent at 21 days and were restored to sham levels by 56 days after MI; the interquartile range of stiffness values was larger in IgG2a-treated infarcts than SYN0012-treated infarcts, which were similar to the range of sham myocardium. Representative Masson’s trichrome–stained sections denote scar location (yellow line), as identified by a custom image processing algorithm (B). Images were used to quantify the fractional scar length as a percentage of cardiac circumference (C) and the average thickness along the infarct length (D). Data are presented as mean ± SEM; each dot represents the average of either 5 independent measurements (A) or 3 independent images (C and D) from individual animals, with n = 3–4. Significance was determined by 2-way ANOVA with Holm-Sidak’s multiple comparison test. *P < 0.05 between treatments, ^P < 0.05 between time points

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