Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease

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 -/-) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 -/- infection showed lower heart-to-body ratio (P<0.01) as well as reduced inflammatory pathology (P<0.05), CCL5 expression (P<0.05), myocyte size (P<0.05) and fibrosis (P<0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P<0.05). Plasma concentration of MMP-2 was higher (P<0.05) in infected WT than in spp1 -/- mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P<0.01) and activity (P<0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 -/- littermates. CCL5 and MMP-2 induction occurred preferentially (P<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 (P<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.

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

“…In aging hearts, osteopontin derived from adipose tissue (and not from the myocardium) was suggested to promote cardiac fibrosis and dysfunction 373 . In a mouse model of Chagas disease, OPN was implicated in cardiac inflammation, fibrosis, and dysfunction 374 . OPN mediated fibrosis in a model of viral myocarditis 375 ; however, in a model of autoimmune myocarditis, osteopontin did not affect inflammation 376 Expression: Upregulated in myocardial infarcts and predominantly localized in activated macrophages 377 , 378 , 379 Role: Protects the infarcted heart from ventricular dilation by promoting collagen deposition 380 i) Stimulation of f fibroblast proliferation through integrin activation 369 , 381 , and protection of fibroblasts from apoptosis 137 .…”

Sialic acid removal by trans-sialidase modulates MMP-2 activity during Trypanosoma cruzi infection

“…[ 2 ]. In Chagas disease, circulating MMP-2 and -9 were proposed as biomarkers for asymptomatic to cardiac form progression [ 5 – 7 ], and alterations in their activity and expression during T. cruzi acute experimental infection have also been observed [ 8 – 11 ].…”

Systematic analysis of long non-coding RNA and mRNA expression changes in ApoE-deficient mice during atherosclerosis

“…Spp1 is a pro-inflammatory cytokine that orchestrates cell recruitment and cardiac architecture. Caballero et al reported that spp1 − / − mice have a low heart-to-body ratio as well as reduced inflammatory pathology, CCL5 expression, myocyte size, and fibrosis in cardiac tissues, leading to the proposal that endogenous Spp1 is a key player in the pathogenesis of chronic Chagas heart disease [43]. Our observation of Spp1 overexpression in ApoE − / − mouse model indicates that Spp1 may accelerate the process of atherosclerosis by inducing inflammation.…”