Osteopontin: a fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host.
The characteristics of dilated cardiomyopathy (DCM) resulting from chronic viral myocarditis are remodeling processes of the extracellular matrix. Based on our findings of enhanced osteopontin (OPN) expression in inflamed human hearts, we further investigated in the murine model of acute and chronic coxsackievirus (CV)B3-myocarditis the role of OPN regarding its involvement in resolution of cardiac virus infection and fibrosis. In hearts of A.BY/SnJ mice susceptible to chronic CVB3-myocarditis, a pronounced increase of OPN expression levels was detected by microarray analysis and quantitative RT-PCR during acute stages of myocarditis. Combined immunohistochemistry and in situ hybridization identified infiltrating macrophages as main OPN producers. In contrast to resistant C57BL/6 and OPN gene-deficient mice, transcription levels of matrix metalloproteinase-3, TIMP1 (tissue inhibitor of metalloproteinases-1), uPA (urokinase-type plasminogen activator), and transforming growth factor beta1 were elevated in susceptible mice, and as a consequence, procollagen-1alpha mRNA expression and fibrosis was considerably enhanced. Treatment of infected susceptible mice with the vitamin D analog ZK 191784 led to decreased myocardial expression levels of OPN, metalloproteinase-3, TIMP1, uPA, and procollagen-1alpha and subsequently to reduced fibrosis. Concurrently, the fibrosis-relevant signaling molecules pERK (phosphorylated extracellular signal-regulated kinase) and pAkt (phosphorylated Akt), increased in A.BY/SnJ mice, were diminished in ZK 191784-treated mice. Here, we show that high expression levels of OPN in acute myocarditis are associated with consecutive development of extensive fibrosis that can be reduced by treatment with a vitamin D analog. Thus, OPN may serve as a diagnostic tool as well as a potential therapeutic target to limit cardiac remodeling in chronic myocarditis.
Szalay
Gudrun
G
Department of Molecular Pathology, Institute for Pathology, University Hospital, Tübingen, Germany.
Sauter
Martina
M
Haberland
Michael
M
Zuegel
Ulrich
U
Steinmeyer
Andreas
A
Kandolf
Reinhard
R
Klingel
Karin
K
D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D002908:Chronic Disease; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003384:Coxsackievirus Infections / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000472:pathogenicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D012333:RNA, Messenger; C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C470666:ZK 191784; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D002117:Calcitriol