Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12-independent manner and worsens tissue remodeling after myocardial infarction
Articolo
Data di Pubblicazione:
2017
Citazione:
Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12-independent manner and worsens tissue remodeling after myocardial infarction / S. Di Maggio, G. Milano, F. De Marchis, A. D'Ambrosio, M. Bertolotti, B.S. Palacios, I. Badi, E. Sommariva, G. Pompilio, M.C. Capogrossi, A. Raucci. - In: BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE. - ISSN 0925-4439. - 1863:11(2017 Nov), pp. 2693-2704.
Abstract:
Myocardial infarction (MI) is a major health burden worldwide. Extracellular High mobility group box 1 (HMGB1) regulates tissue healing after injuries. The reduced form of HMGB1 (fr-HMGB1) exerts chemotactic activity by binding CXCL12 through CXCR4, while the disulfide form, (ds-HMGB1), induces cytokines expression by TLR4. Here, we assessed the role of HMGB1 redox forms and the non-oxidizable mutant (3S) on human cardiac fibroblast (hcFbs) functions and cardiac remodeling after infarction. Among HMGB1 receptors, hcFbs express CXCR4. Fr-HMGB1 and 3S, but not ds-HMGB1, promote hcFbs migration through Src activation, while none of HMGB1 redox forms induces proliferation or inflammatory mediators. 3S is more effective than fr-HMGB1 in stimulating hcFbs migration and Src phosphorylation being active at lower concentrations and in oxidizing conditions. Notably, chemotaxis toward both proteins is CXCR4-dependent but, in contrast to fr-HMGB1, 3S does not require CXCL12 since hcFbs migration persists in the presence of the CXCL12/CXCR4 inhibitor AMD3100 or an anti-CXCL12 antibody. Interestingly, 3S interacts with CXCR4 and induces a different receptor conformation than CXCL12. Mice undergoing MI and receiving 3S exhibit adverse LV remodeling owing to an excessive collagen deposition promoted by a higher number of myofibroblasts. On the contrary, fr-HMGB1 ameliorates cardiac performance enhancing neoangiogenesis and reducing the infarcted area and fibrosis. Altogether, our results demonstrate that non-oxidizable HMGB1 induce a sustained cardiac fibroblasts migration despite the redox state of the environment and by altering CXCL12/CXCR4 axis. This affects proper cardiac remodeling after an infarction.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Cardiac fibroblasts; Cardiac remodeling; CXCR4; Myocardial infarction; Oxidation; Molecular Medicine; Molecular Biology
Elenco autori:
S. Di Maggio, G. Milano, F. De Marchis, A. D'Ambrosio, M. Bertolotti, B.S. Palacios, I. Badi, E. Sommariva, G. Pompilio, M.C. Capogrossi, A. Raucci
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