title: Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation.
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.
authors.affiliation: 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.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Lynch
authors.affiliation: Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Mohamed Ameen
authors.initials: MA
authors.lastname: Ismahil
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.affiliation: Department of Public Health Sciences, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zilliox
authors.affiliation: Kerckhoff Heart and Thorax Center, Department of Cardiology, Bad Nauheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Troidl
authors.affiliation: Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.affiliation: Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA. Electronic address: sadayasl@ucmail.uc.edu.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sadayappan
mesh_terms: D000818:Animals; D015415:Biomarkers; D002311:Cardiomyopathy, Dilated / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D009205:Myocarditis / Q000209:etiology* / Q000378:metabolism; D013163:Splenomegaly; D018754:Ventricular Dysfunction; D000099163:Myosin Binding Protein C
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D000099163:Myosin Binding Protein C
keywords: Dilated cardiomyopathy; Inflammation; MYBPC3; Mouse models; Sarcomere biology