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Published on: June 3, 2018
Imatinib mesylate attenuates fibrosis in coxsackievirus b3-induced chronic myocarditis
Carola Leipner1, Katja Grün, Andreas Müller
1Institute of Virology, Medical Faculty, Friedrich Schiller University, Jena, Germany.
Insights
Platelet-derived growth factor (PDGF) inhibition reduced cardiac fibrosis in mice with chronic myocarditis. Imatinib treatment attenuated fibrosis by inhibiting PDGF receptor signaling, suggesting a causal role for PDGF in heart disease.
Area of Science:
- Cardiovascular Research
- Immunology
- Molecular Biology
Background:
- Coxsackievirus B3 (CVB3) infection causes chronic myocarditis, characterized by cardiac fibrosis and elevated platelet-derived growth factor (PDGF).
- PDGF signaling is implicated in fibroblast activation and extracellular matrix deposition, key components of fibrosis.
Purpose of the Study:
- To investigate the causal role of PDGF in CVB3-induced cardiac fibrosis.
- To evaluate the efficacy of inhibiting PDGF receptor signaling using Imatinib in a mouse model of chronic myocarditis.
Main Methods:
- CVB3 infection was induced in MHC class II knockout mice.
- Mice were treated with Imatinib (a PDGF receptor kinase inhibitor) or vehicle.
- Cardiac fibrosis was assessed via Sirius-Red staining and hydroxyproline content.
- PDGF receptor activation, inflammatory cytokines, viral load, and matrix metalloproteinase (MMP) activity were analyzed.
Main Results:
- Imatinib treatment significantly reduced cardiac fibrosis, Sirius Red staining, and hydroxyproline content.
- PDGF receptor phosphorylation was inhibited by Imatinib, but viral titers and inflammatory infiltrates remained unaffected.
- Expression of fibronectin and tenascin C was reduced in Imatinib-treated mice.
- MMP activity was not elevated, indicating fibrosis reduction was not due to increased matrix degradation.
Conclusions:
- Elevated PDGF expression and receptor activity play a causal role in the pathogenesis of cardiac fibrosis.
- Inhibiting PDGF receptor signaling is a potential therapeutic strategy for mitigating cardiac fibrosis in myocarditis.
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(0)/Aa(0)) 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. PDGFalpha 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 PDGFalpha 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 microMol/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.
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