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J Mol Cell Cardiol. 2017 Jan;102:83-93. doi: 10.1016/j.yjmcc.2016.12.002. Epub 2016 Dec 10.

Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation.

Author information

1
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53715, USA.
2
Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
3
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
4
Department of Public Health Sciences, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
5
Kerckhoff Heart and Thorax Center, Department of Cardiology, Bad Nauheim, Germany.
6
Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA. Electronic address: sadayasl@ucmail.uc.edu.

Abstract

Cardiomyopathies are a leading cause of heart failure and are often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. To determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C(t/t) mouse model of DCM at 3months of age. Compared to wild type (WT) mice, DCM mice exhibited significantly decreased fractional shortening (36.4±2% vs. 15.5±1.0%, p<0.0001) and significantly increased spleen weight (5.3±0.3 vs. 7.2±0.4mg/mm, p=0.002). Intriguingly, flow cytometry analysis revealed a significant increase in total (CD45+CD11b+Ly6C-MHCII+F480+) macrophages (6.5±1.4% vs. 14.8±1.4%, p=0.002) and classically activated (CD45+CD11b+Ly6C-MHCII+F480+CD206-) proinflammatory (M1) macrophages (3.4±0.8% vs. 10.3±1.2%, p=0.0009) in DCM hearts as compared with WT hearts. These results were further confirmed by immunofluorescence analysis of heart tissue sections. Splenic red pulp (CD11b+Ly6C+MHCIIlowF480hi) macrophages were significantly elevated (1.3±0.1% vs. 2.4±0.1%, p=0.0001) in DCM compared to WT animals. Serum cytokine analysis in DCM animals exhibited a significant increase (0.65±0.2 vs. 2.175±0.5pg/mL, p=0.02) in interleukin (IL)-6 compared to WT animals. Furthermore, RNA-seq analysis revealed the upregulation of inflammatory pathways in the DCM hearts. Together, these data indicate a robust proinflammatory response in DCM hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction.

KEYWORDS:

Dilated cardiomyopathy; Inflammation; MYBPC3; Mouse models; Sarcomere biology

PMID:
27955979
PMCID:
PMC5316303
DOI:
10.1016/j.yjmcc.2016.12.002
[Indexed for MEDLINE]
Free PMC Article

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