Imatinib mesylate attenuates fibrosis in coxsackievirus b3-induced chronic myocarditis
| Autor: | Laura Borsi, Katja Grün, Michael Kiehntopf, Alexander Berndt, Hartwig Kosmehl, Andreas Müller, Frank-D. Böhmer, Elisabeth Buchdunger, Andrea Uecker, Carola Leipner, Tobias Janik |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Platelet-derived growth factor Physiology Cardiac fibrosis Coxsackievirus Infections Tenascin Piperazines Proinflammatory cytokine Mice chemistry.chemical_compound Fibrosis Physiology (medical) Internal medicine Animals Medicine Receptors Platelet-Derived Growth Factor Protein Kinase Inhibitors Mice Knockout Platelet-Derived Growth Factor Lymphokines biology business.industry Myocardium Tenascin C Heart Proto-Oncogene Proteins c-sis medicine.disease Enterovirus B Human Disease Models Animal Myocarditis Pyrimidines Endocrinology Imatinib mesylate chemistry Benzamides Imatinib Mesylate biology.protein Cardiology and Cardiovascular Medicine business Platelet-derived growth factor receptor Signal Transduction |
| Zdroj: | Cardiovascular Research. 79:118-126 |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | Aims Coxsackievirus B3 (CVB3)-induced chronic myocarditis in mice is accompanied by severe fibrosis and by sustained elevation of platelet-derived growth factor (PDGF)-A, -B, and -C levels in the cardiac tissue. To test if PDGF stimulation of resident fibroblasts causally contributes to fibrosis, we employed inhibition of PDGF receptor signalling with the orally available kinase inhibitor Imatinib. Methods and results Chronic myocarditis was induced by CVB3 infection of major histocompatibility complex (MHC) class II knockout (B6Aa/Aa) mice. The mice were treated with 100 mg/kg Imatinib or vehicle, respectively, twice daily for 34 days. Expression of PDGF-C and of inflammatory cytokines were analysed by semi-quantitative RT–PCR. PDGFα receptor phosphorylation was detected by immunoblotting of cardiac tissue extracts and in situ by immunohistochemistry. Fibrosis formation was analysed by Sirius-Red staining and hydroxyproline (HP) determination. Fibronectin, and tenascin expression was analysed by RT–PCR and immunohistochemistry. Matrix metalloproteinase (MMP) activity was assessed with collagen, synthetic peptides, and gelatine as substrates. Imatinib significantly inhibited the myocarditis-related PDGFα receptor activation in the heart tissue. The virus titres in the hearts, inflammatory infiltrations, and elevated PDGF levels were unaffected by the Imatinib treatment. A significant attenuation of fibrosis occurred in Imatinib-treated animals. The Sirius Red-stained fibrotic area was reduced from 5.30 ± 0.50 to 3.21 ± 0.35%, and the HP content was reduced from 362 ± 43 to 238 ± 32 µMol/10 mg dry weight vs. 190 ± 27 in uninfected controls. The expression of fibronectin, EIIIA+ fibronectin, and tenascin C were likewise reduced. The diminished matrix protein deposition was not caused by elevated MMP activity, since MMP activity was not changed or even reduced under Imatinib. Conclusion The data suggest a causal role for elevated PDGF expression and PDGF receptor activity in the pathogenesis of cardiac fibrosis. |
| Databáze: | OpenAIRE |
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