title: Ectopic trypsin in the myocardium promotes dilated cardiomyopathy after influenza A virus infection.
abstract: We have previously reported that ectopic trypsin in the myocardium triggers acute myocarditis after influenza A virus (IAV) infection. As myocarditis is a common precursor to dilated cardiomyopathy (DCM), the aim of the present study was to investigate the influence of trypsin on the progression of DCM after IAV infection. IAV-infected mice treated with saline or trypsin inhibitor were euthanized on days 0, 9, 20, 40 and 60 postinfection. Trypsin expression colocalized with myocardial inflammatory loci and IAV-induced myocarditis peaked on day 9 postinfection and alleviated by day 20 but persisted until day 60 postinfection, even though replication of IAV was not detected from day 20 postinfection. Similar time courses were observed for the activation of pro-matrix metalloproteinase (pro-MMP)-9 and expression of the proinflammatory cytokines IL-6, IL-1β, and TNF-α. Degradation of collagen type I, proliferation of ventricular interstitial collagen, and expression of collagen type I and III mRNA increased significantly during acute and chronic phases; collagen type III mRNA increased more significantly than collagen type I mRNA. Cardiac function progressively deteriorated with progressive left ventricular dilation. The trypsin inhibitor aprotinin suppressed pro-MMP-9 activation and cytokine release, alleviated myocardial inflammation, and restored collagen metabolism during acute and chronic phases of myocarditis. This effectively prevented ventricular dilation and improved cardiac function. These results suggest that ectopic trypsin in the myocardium promoted DCM through chronic activation of pro-MMP-9, persistent induction of cytokines, and mediation of collagen remodeling. Pharmacological inhibition of trypsin activity might be a promising approach for the prevention of viral cardiomyopathy.
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Institute of Cardiovascular Research, Nantong University, Jiangsu, China; and.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Pan
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Institute of Cardiovascular Research, Nantong University, Jiangsu, China; and.
authors.forename: Hua-Mei
authors.initials: HM
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Institute of Cardiovascular Research, Nantong University, Jiangsu, China; and.
authors.forename: Lu-Jing
authors.initials: LJ
authors.lastname: Xue
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Institute of Cardiovascular Research, Nantong University, Jiangsu, China; and.
authors.forename: Min
authors.initials: M
authors.lastname: Pan
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Institute of Cardiovascular Research, Nantong University, Jiangsu, China; and.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kido
authors.affiliation: Department of Cardiology, Affiliated Hospital of Nantong University, Institute of Cardiovascular Research, Nantong University, Jiangsu, China; and dr.zhujianhua@gmail.com.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control* / Q000821:virology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004792:Enzyme Precursors / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000517:prevention & control / Q000821:virology; D018836:Inflammation Mediators / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control* / Q000821:virology; D009206:Myocardium / Q000201:enzymology*; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000517:prevention & control / Q000821:virology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D014779:Virus Replication
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D004792:Enzyme Precursors; C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D014361:Trypsin Inhibitors; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D014357:Trypsin; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: dilated cardiomyopathy; extracellular matrix remodeling; influenza virus; myocarditis; trypsin