Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation

Thomas L. Lynch, Mohamed Ameen Ismahil, Anil G. Jegga, Michael J. Zilliox, Christian Troidl, Sumanth D. Prabhu, Sakthivel Sadayappan

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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 3 months 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 ± 0.4 mg/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 ± 0.5 pg/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.

Original languageEnglish
Pages (from-to)83-93
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume102
DOIs
StatePublished - Jan 1 2017

Keywords

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

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