Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 102, Issue -, Pages 83-93Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2016.12.002
Keywords
Dilated-cardiomyopathy; Inflammation; Sarcomere biology; MYBPC3; Mouse models
Categories
Funding
- National Institutes of Health [R01s HL105826, HL130356, K02 HL114749, R01 HL125735]
- VA Merit [I01 BX002706]
- American Heart Association [15PRE22430028]
- [14GRNT20490025]
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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-CM) 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(+) CD11(b+) Ly6C(-) MHCII+ F480(+)) macrophages (6.5 +/- 1A% 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 +/- 12%, 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 (CD11(b+) Ly6C(+)MHCII(low)F480(hi)) 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. (C) 2016 The Authors. Published by Elsevier Ltd.
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