Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12-independent manner and worsens tissue remodeling after myocardial infarction

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

Di Maggio, Stefania¹  Milano, Giuseppina^2,3  De Marchis, Francesco⁴  D'Ambrosio, Alessandro¹  Bertolotti, Matteo¹  Soler Palacios, Blanca⁵  Badi, Ileana¹  Sommariva, Elena²  Pompilio, Giulio^2,6  Capogrossi, Maurizio C.⁷  Raucci, Angela¹ 

[1] IRCCS, Ctr Cardiol Monzino, Unit Expt Cardiooncol & Cardiovasc Aging, Milan, Italy

[2] IRCCS, Ctr Cardiol Monzino, Vasc Biol & Regenerat Med Unit, Milan, Italy

[3] Univ Hosp Lausanne, Dept Surg & Anesthesiol, Lab Cardiovasc Res, Lausanne, Switzerland

[4] Ist Sci San Raffaele, Div Genet & Cell Biol, Milan, Italy

[5] CSIC, Ctr Nacl Biotecnol, Dept Immunol & Oncol, Cantoblanco Campus, Madrid, Spain

[6] Univ Milan, Dipartimento Sci Cliniche & Comunita, Milan, Italy

[7] IRCCS, Ist Dermopat Immacolata, Lab Vasc Pathol, Rome, Italy

关键词: Cardiac fibroblasts;    Cardiac remodeling;    Oxidation;    Myocardial infarction;    CXCR4;   

DOI  :  10.1016/j.bbadis.2017.07.012

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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