Journal article
Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12-independent manner and worsens tissue remodeling after myocardial infarction.
- Di Maggio S Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
- Milano G Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy; Laboratory of Cardiovascular Research, Department of Surgery and Anesthesiology, University Hospital Lausanne, Lausanne, Switzerland.
- De Marchis F Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
- D'Ambrosio A Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
- Bertolotti M Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
- Palacios BS Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco Campus, Madrid, Spain.
- Badi I Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
- Sommariva E Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
- Pompilio G Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy; Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy.
- Capogrossi MC Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
- Raucci A Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy. Electronic address: araucci@ccfm.it.
- 2017-07-19
Published in:
- Biochimica et biophysica acta. Molecular basis of disease. - 2017
CXCR4
Cardiac fibroblasts
Cardiac remodeling
Myocardial infarction
Oxidation
Cell Movement
Chemokine CXCL12
Female
Fibroblasts
HMGB1 Protein
Humans
Male
Myocardial Infarction
Myocardium
Oxidation-Reduction
Receptors, CXCR4
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.bbadis.2017.07.012
- PMID 28716707
- Persistent URL
- https://sonar.ch/global/documents/123142
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