ABSTRACT
Inflammatory processes of the heart are often induced by viruses. Although most acute virus-induced myocarditis quickly resolves, some patients develop chronic myocarditis resulting in a considerable disruption of the myocardial matrix network, finally leading to cardiac dysfunction. The death of cardiomyocytes due to virus replication is followed by the attraction of macrophages and T cells to the sites of cardiac damage. Ongoing inflammation is usually suppressed by interleukin-10 and transforming growth factor-β production, thus activating myofibroblasts and secretion of extracellular matrix proteins like collagen type I. Also, osteopontin (OPN), a matricellular protein with cytokine-like properties, is critically involved in inflammatory pathways and can modulate the cell biology of cardiac repair. In our model of coxsackievirus B3–induced myocarditis, we have shown that increased early OPN expression in macrophages is a determinant of fibrosis and enhanced cardiac remodeling. OPN was not found to influence the efficacy of the antiviral immune response. Also, in patients with acute and chronic myocarditis, but not in patients with end-stage dilated cardiomyopathy, we found a high OPN expression in macrophages, indicating active inflammatory processes. Thus cardiac OPN expression might be considered as a biomarker indicating ongoing cardiac inflammation preceding fibrosis and remodeling of the heart.
KEYWORDS
Osteopontin - inflammation - virus myocarditis - fibrosis - cardiac remodeling
REFERENCES
-
1
Martino T A, Liu P, Sole M J.
Viral infection and the pathogenesis of dilated cardiomyopathy.
Circ Res.
1994;
74(2)
182-188
-
2
Mason J W.
Myocarditis and dilated cardiomyopathy: an inflammatory link.
Cardiovasc Res.
2003;
60(1)
5-10
-
3
Cocker M S, Abdel-Aty H, Strohm O, Friedrich M G.
Age and gender effects on the extent of myocardial involvement in acute myocarditis: a cardiovascular magnetic resonance study.
Heart.
2009;
95(23)
1925-1930
-
4
Mahrholdt H, Wagner A, Deluigi C C et al..
Presentation, patterns of myocardial damage, and clinical course of viral myocarditis.
Circulation.
2006;
114(15)
1581-1590
-
5 Knipe D M, Howley P M. Fields Virology. 4th ed. Philadelphia, PA; Lippincott-Raven 2001
-
6
Klingel K, Sauter M, Bock C T, Szalay G, Schnorr J J, Kandolf R.
Molecular pathology of inflammatory cardiomyopathy.
Med Microbiol Immunol (Berl).
2004;
193(2-3)
101-107
-
7
Grist N R, Bell E J, Assaad F.
Enteroviruses in human disease.
Prog Med Virol.
1978;
24
114-157
-
8
Kindermann I, Kindermann M, Kandolf R et al..
Predictors of outcome in patients with suspected myocarditis.
Circulation.
2008;
118(6)
639-648
-
9
Klingel K, Hohenadl C, Canu A et al..
Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation.
Proc Natl Acad Sci U S A.
1992;
89(1)
314-318
-
10
Fairweather D, Frisancho-Kiss S, Yusung S A et al..
Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart.
Am J Pathol.
2004;
165(6)
1883-1894
-
11
Szalay G, Sauter M, Hald J, Weinzierl A, Kandolf R, Klingel K.
Sustained nitric oxide synthesis contributes to immunopathology in ongoing myocarditis attributable to interleukin-10 disorders.
Am J Pathol.
2006;
169(6)
2085-2093
-
12
Li J, Schwimmbeck P L, Tschope C et al..
Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction.
Cardiovasc Res.
2002;
56(2)
235-247
-
13
Heymans S, Pauschinger M, De Palma A et al..
Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis.
Circulation.
2006;
114(6)
565-573
-
14
Lang C, Sauter M, Szalay G et al..
Connective tissue growth factor: a crucial cytokine-mediating cardiac fibrosis in ongoing enterovirus myocarditis.
J Mol Med.
2008;
86(1)
49-60
-
15
Mazzali M, Kipari T, Ophascharoensuk V et al..
Osteopontin—a molecule for all seasons.
QMJ.
2002;
95
3-13
-
16
O'Regan A W, Chupp G L, Lowry J A, Goetschkes M, Mulligan N, Berman J S.
Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro.
J Immunol.
1999;
162(2)
1024-1031
-
17
Graf K, Stawowy P.
Osteopontin: a protective mediator of cardiac fibrosis?.
Hypertension.
2004;
44(6)
809-810
-
18
Wang K X, Denhardt D T.
Osteopontin: role in immune regulation and stress responses.
Cytokine Growth Factor Rev.
2008;
19(5-6)
333-345
-
19
Okamoto H.
Osteopontin and cardiovascular system.
Mol Cell Biochem.
2007;
300(1–2)
1-7
-
20
Giachelli C M, Liaw L, Murry C E, Schwartz S M, Almeida M.
Osteopontin expression in cardiovascular diseases.
Ann N Y Acad Sci.
1995;
760
109-126
-
21
Singh K, Sirokman G, Communal C et al..
Myocardial osteopontin expression coincides with the development of heart failure.
Hypertension.
1999;
33(2)
663-670
-
22
Trueblood N A, Xie Z, Communal C et al..
Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin.
Circ Res.
2001;
88(10)
1080-1087
-
23
Murry C E, Giachelli C M, Schwartz S M, Vracko R.
Macrophages express osteopontin during repair of myocardial necrosis.
Am J Pathol.
1994;
145(6)
1450-1462
-
24
Williams E B, Halpert I, Wickline S, Davison G, Parks W C, Rottman J N.
Osteopontin expression is increased in the heritable cardiomyopathy of Syrian hamsters.
Circulation.
1995;
92(4)
705-709
-
25
Shin T, Ahn M, Kim H, Kim H M, Matsumoto Y.
Increased expression of osteopontin in the heart tissue of Lewis rats with experimental autoimmune myocarditis.
J Vet Med Sci.
2006;
68(4)
379-382
-
26
Szalay G, Sauter M, Haberland M et al..
Osteopontin: a fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host.
Circ Res.
2009;
104(7)
851-859
-
27
Mukherjee B B, Nemir M, Beninati S et al..
Interaction of osteopontin with fibronectin and other extracellular matrix molecules.
Ann N Y Acad Sci.
1995;
760
201-212
-
28
Kaartinen M T, Pirhonen A, Linnala-Kankkunen A, Mäenpää P H.
Cross-linking of osteopontin by tissue transglutaminase increases its collagen binding properties.
J Biol Chem.
1999;
274(3)
1729-1735
-
29
Lenga Y, Koh A, Perera A S, McCulloch C A, Sodek J, Zohar R.
Osteopontin expression is required for myofibroblast differentiation.
Circ Res.
2008;
102(3)
319-327
-
30
O'Regan A, Berman J S.
Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation.
Int J Exp Pathol.
2000;
81(6)
373-390
-
31
Scatena M, Liaw L, Giachelli C M.
Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease.
Arterioscler Thromb Vasc Biol.
2007;
27(11)
2302-2309
-
32
Ashkar S, Weber G F, Panoutsakopoulou V et al..
Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity.
Science.
2000;
287(5454)
860-864
-
33
Yu Q, Vazquez R, Khojeini E V, Patel C, Venkataramani R, Larson D F.
IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice.
Am J Physiol Heart Circ Physiol.
2009;
297(1)
H76-H85
-
34
Abel B, Freigang S, Bachmann M F, Boschert U, Kopf M.
Osteopontin is not required for the development of Th1 responses and viral immunity.
J Immunol.
2005;
175(9)
6006-6013
-
35
Abel B, Kurrer M, Shamshiev A et al..
The osteopontin-CD44 pathway is superfluous for the development of autoimmune myocarditis.
Eur J Immunol.
2006;
36
494-499
-
36
Shinohara M L, Lu L, Bu J et al..
Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells.
Nat Immunol.
2006;
7(5)
498-506
-
37
Satoh M, Nakamura M, Akatsu T, Shimoda Y, Segawa I, Hiramori K.
Myocardial osteopontin expression is associated with collagen fibrillogenesis in human dilated cardiomyopathy.
Eur J Heart Fail.
2005;
7(5)
755-762
-
38
Stawowy P, Blaschke F, Pfautsch P et al..
Increased myocardial expression of osteopontin in patients with advanced heart failure.
Eur J Heart Fail.
2002;
4(2)
139-146
-
39
Atalar E, Ozturk E, Ozer N et al..
Plasma soluble osteopontin concentrations are increased in patients with rheumatic mitral stenosis and associated with the severity of mitral valve calcium.
Am J Cardiol.
2006;
98(6)
817-820
-
40
Canver C C, Gregory R D, Cooler S D, Voytovich M C.
Association of osteopontin with calcification in human mitral valves.
J Cardiovasc Surg (Torino).
2000;
41(2)
171-174
-
41
Georgiadou P, Iliodromitis E K, Varounis C et al..
Relationship between plasma osteopontin and oxidative stress in patients with coronary artery disease.
Expert Opin Ther Targets.
2008;
12(8)
917-920
-
42
Suezawa C, Kusachi S, Murakami T et al..
Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: correlation with left-ventricular volume and function.
J Lab Clin Med.
2005;
145(1)
33-40
-
43
Arnlöv J, Evans J C, Benjamin E J et al..
Clinical and echocardiographic correlates of plasma osteopontin in the community: the Framingham Heart Study.
Heart.
2006;
92(10)
1514-1515
-
44
Bazzichi L, Ghiadoni L, Rossi A et al..
Osteopontin is associated with increased arterial stiffness in rheumatoid arthritis.
Mol Med.
2009;
15(11–12)
402-406
-
45
Chen Y J, Shen J L, Wu C Y, Chang Y T, Chen C M, Lee F Y.
Elevated plasma osteopontin level is associated with occurrence of psoriasis and is an unfavorable cardiovascular risk factor in patients with psoriasis.
J Am Acad Dermatol.
2009;
60(2)
225-230
-
46
Schoensiegel F, Bekeredjian R, Schrewe A et al..
Atrial natriuretic peptide and osteopontin are useful markers of cardiac disorders in mice.
Comp Med.
2007;
57(6)
546-553
Professor Dr. Karin KlingelM.D.
Department of Molecular Pathology, University Hospital Tübingen
Liebermeisterstr. 8, D-72076 Tübingen, Germany
Email: karin.klingel@med.uni-tuebingen.de
