Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation Journal Article

Authors: Lynch, T. L., 4th; Ismahil, M. A.; Jegga, A. G.; Zilliox, M. J.; Troidl, C.; Prabhu, S. D.; Sadayappan, S
Article 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%, p0.0001) 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: Inflammation; MYBPC3; Mouse models; Public Health Services; Dilated cardiomyopathy; Sarcomere biology
Journal Title: Journal of Molecular and Cellular Cardiology
Volume: 102
ISSN: 1095-8584; 0022-2828
Publisher: The Authors. Published by Elsevier Ltd.  
Journal Place: England
Date Published: 2017
Start Page: 83
End Page: 93
Language: eng
Notes: LR: 20170303; CI: Copyright A(c) 2016; GR: K02 HL114749/HL/NHLBI NIH HHS/United States; GR: I01 BX002706/BX/BLRD VA/United States; GR: R01 HL130356/HL/NHLBI NIH HHS/United States; GR: R01 HL125735/HL/NHLBI NIH HHS/United States; GR: R01 HL105826/HL/NHLBI NIH HHS/United States; JID: 0262322; NIHMS838375; OTO: NOTNLM; PMCR: 2018/01/01; 2016/10/01 [received]; 2016/12/06 [revised]; 2016/12/08 [accepted]; ppublish