title: The role of Interleukin Receptor Associated Kinase (IRAK)-M in regulation of myofibroblast phenotype in vitro, and in an experimental model of non-reperfused myocardial infarction.
abstract: In the infarcted myocardium, necrotic cardiomyocytes activate innate immune pathways, stimulating pro-inflammatory signaling cascades. Although inflammation plays an important role in clearance of the infarct from dead cells and matrix debris, repair of the infarcted heart requires timely activation of signals that negatively regulate the innate immune response, limiting inflammatory injury. We have previously demonstrated that Interleukin receptor-associated kinase (IRAK)-M, a member of the IRAK family that suppresses toll-like receptor/interleukin-1 signaling, is upregulated in the infarcted heart in both macrophages and fibroblasts, and restrains pro-inflammatory activation attenuating adverse remodeling. Although IRAK-M is known to suppress inflammatory activation of macrophages, its role in fibroblasts remains unknown. Our current investigation examines the effects of IRAK-M on fibroblast phenotype and function. In vitro, IRAK-M null cardiac fibroblasts have impaired capacity to contract free-floating collagen pads. IRAK-M loss reduces transforming growth factor (TGF)-β-mediated α-smooth muscle actin (α-SMA) expression. IRAK-M deficient cardiac fibroblasts exhibit a modest reduction in TGF-β-stimulated Smad activation and increased expression of the α-SMA repressor, Y-box binding protein (YB)-1. In a model of non-reperfused myocardial infarction, IRAK-M absence does not affect collagen content and myofibroblast density in the infarcted and remodeling myocardium, but increases YB-1 levels and is associated with attenuated α-SMA expression in isolated infarct myofibroblasts. Our findings suggest that, in addition to its role in restraining inflammation following reperfused infarction, IRAK-M may also contribute to myofibroblast conversion.
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States.
authors.forename: Amit
authors.initials: A
authors.lastname: Saxena
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States.
authors.forename: Arti V
authors.initials: AV
authors.lastname: Shinde
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States.
authors.forename: Zaffar
authors.initials: Z
authors.lastname: Haque
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States.
authors.forename: Yi-Jin
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States; Division of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States.
authors.forename: Ya
authors.initials: Y
authors.lastname: Su
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States. Electronic address: nikolaos.frangogiannis@einstein.yu.edu.
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D000818:Animals; D002452:Cell Count; D002469:Cell Separation; D048429:Cell Size / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D010477:Perfusion; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D051840:Y-Box-Binding Protein 1; D003094:Collagen; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse
keywords: Innate immunity; Interleukin receptor-associated kinase (IRAK)-M; Myocardial infarction; Myofibroblast; Transforming growth factor (TGF)-β; α-Smooth muscle actin