title: In vivo delivery of adenoviral vector containing interleukin-17 receptor a reduces cardiac remodeling and improves myocardial function in viral myocarditis leading to dilated cardiomyopathy.
abstract: Th17 cells have been implicated in the pathogenesis of myocarditis. Interleukin (IL)-17A produced by Th17 cells is dispensable for viral myocarditis but essential for the progression to dilated cardiomyopathy (DCM). This study investigated whether the adenoviral transfer of the IL-17 receptor A reduces myocardial remodeling and dysfunction in viral myocarditis leading to DCM. In a mouse model of Coxsackievirus B3 (CVB3)-induced chronic myocarditis, the delivery of the adenovirus-containing IL-17 receptor A (Ad-IL17RA:Fc) reduced IL-17A production and decreased the number of Th17 cells in the spleen and heart, leading to the down-regulation of systemic TNF-α and IL-6 production. Cardiac function improved significantly in the Ad-IL17R:Fc- compared with the Ad-null-treated mice 3 months after the first CVB3 infection. Ad-IL17R:Fc reduced the left ventricle dilation and decreased the mortality in viral myocarditis, leading to DCM (56% in the Ad-IL17R:Fc versus 76% in the Ad-null group). The protective effects of Ad-IL17R-Fc on remodeling correlated with the attenuation of myocardial collagen deposition and the reduction of fibroblasts in CVB3-infected hearts, which was accompanied by the down-regulation of A distintegrin and metalloprotease with thrombospondin type 1 motifs (ADAMTS-1), Matrix metalloproteinase-2(MMP-2), and collagen subtypes I and III in the heart. Moreover, in cultured cardiac fibroblasts, IL-17A induced the expression of ADAMTS-1, MMP-2, and collagen subtypes I and III and increased the proliferation of fibroblasts. We determined that the delivery of IL-17-RA:Fc reduces cardiac remodeling, improves function, and decreases mortality in viral myocarditis leading to DCM, possibly by suppressing fibrosis. Therefore, the adenoviral transfer of the IL-17 receptor A may represent an alternative therapy for chronic viral myocarditis and its progression to DCM.
authors: Key Laboratory of Viral Heart Diseases, Ministry of Public Health, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China ; Department of Cardiology, Xinhua Hospital affiliated to Shanghai Jiaotong University, Shanghai, China.
authors: Yuquan
authors: Y
authors: Xie
authors: Minghui
authors: M
authors: Li
authors: Xinggang
authors: X
authors: Wang
authors: Xian
authors: X
authors: Zhang
authors: Tianqing
authors: T
authors: Peng
authors: Yingzhen
authors: Y
authors: Yang
authors: Yunzeng
authors: Y
authors: Zou
authors: Junbo
authors: J
authors: Ge
authors: Haozhu
authors: H
authors: Chen
authors: Ruizhen
authors: R
authors: Chen
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000276:immunology / Q000628:therapy* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D020381:Interleukin-17 / Q000097:blood; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000276:immunology / Q000628:therapy* / Q000821:virology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053722:Receptors, Interleukin-17 / Q000096:biosynthesis / Q000235:genetics*; D058504:Th17 Cells / Q000276:immunology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; D053722:Receptors, Interleukin-17; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
references: Inflamm Bowel Dis. 2006 May;12(5):382-8
references: 16670527
references: Am J Physiol Heart Circ Physiol. 2002 Mar;282(3):H983-9
references: 11834496
references: Cardiol Rev. 2007 Jul-Aug;15(4):170-7
references: 17575480
references: Cardiovasc Res. 2009 Nov 1;84(2):209-17
references: 19546173
references: Adv Immunol. 2008;99:95-114
references: 19117533
references: Circ Res. 2010 May 28;106(10):1646-55
references: 20378858
references: J Virol. 2002 Nov;76(21):10785-90
references: 12368321
references: Chin Med J (Engl). 2004 Aug;117(8):1228-31
references: 15361300
references: Exp Mol Pathol. 2009 Dec;87(3):212-8
references: 19527710
references: Nat Immunol. 2007 Apr;8(4):345-50
references: 17375096
references: J Biol Chem. 2003 Jun 27;278(26):23656-65
references: 12716911
references: Nat Rev Immunol. 2010 Oct;10(10):712-23
references: 20865019
references: J Exp Med. 2001 Aug 20;194(4):519-27
references: 11514607
references: Eur J Pharmacol. 2011 May 11;658(2-3):168-74
references: 21371462
references: Immunol Cell Biol. 2012 Apr;90(4):421-8
references: 21691280
references: J Virol. 1995 Nov;69(11):6720-8
references: 7474082
references: Circulation. 2010 Apr 20;121(15):1746-55
references: 20368519
references: Eur J Immunol. 2006 Nov;36(11):2849-56
references: 17039570
references: Immunol Rev. 2008 Dec;226:87-102
references: 19161418
references: Semin Immunol. 2007 Dec;19(6):409-17
references: 18053739
references: Virology. 2011 Dec 5;421(1):78-84
references: 21993400
references: Zhonghua Xin Xue Guan Bing Za Zhi. 2007 Sep;35(9):854-8
references: 18070483
references: J Immunol. 2008 Feb 15;180(4):2686-95
references: 18250481
references: FEBS Lett. 2000 Aug 4;478(3):241-5
references: 10930576
references: Circulation. 2003 Jan 21;107(2):320-5
references: 12538435
references: Nat Immunol. 2005 Nov;6(11):1123-32
references: 16200070
references: N Engl J Med. 2000 Nov 9;343(19):1388-98
references: 11070105