Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8258765 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2018 | 55 Pages |
Abstract
Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 â/â) mice were parasite-infected (Brazil strain) for 100Â days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 â/â infection showed lower heart-to-body ratio (PÂ <Â 0.01) as well as reduced inflammatory pathology (PÂ <Â 0.05), CCL5 expression (PÂ <Â 0.05), myocyte size (PÂ <Â 0.05) and fibrosis (PÂ <Â 0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (PÂ <Â 0.05). Plasma concentration of MMP-2 was higher (PÂ <Â 0.05) in infected WT than in spp1 â/â mice. Coincidently, specific immunostaining revealed increased gelatinase expression (PÂ <Â 0.01) and activity (PÂ <Â 0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 â/â littermates. CCL5 and MMP-2 induction occurred preferentially (PÂ <Â 0.01) in WT heart-invading CD8+ T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (PÂ <Â 0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis.
Keywords
MMP-2Jun NH2-terminal kinaseTPA-responsive elementOPNCcl5AP-1DPIJnkMAPKOsteopontininflammationstandard deviationCardiac remodelingANOVAone-way analysis of varianceTrypanosoma cruzidays post infectionTREMatrix metalloproteinase-2wild-typeactivator protein 1mitogen-activated protein kinaseChagas cardiomyopathy
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Authors
Eugenia Pérez Caballero, Miguel H. SantamarÃa, Ricardo S. Corral,