title: HMGB1 attenuates cardiac remodelling in the failing heart via enhanced cardiac regeneration and miR-206-mediated inhibition of TIMP-3.
abstract: OBJECTIVE
  HMGB1 injection into the mouse heart, acutely after myocardial infarction (MI), improves left ventricular (LV) function and prevents remodeling. Here, we examined the effect of HMGB1 in chronically failing hearts.
  
  
  RESULTS
  Adult C57 BL16 female mice underwent coronary artery ligation; three weeks later 200 ng HMGB1 or denatured HMGB1 (control) were injected in the peri-infarcted region of mouse failing hearts. Four weeks after treatment, both echocardiography and hemodynamics demonstrated a significant improvement in LV function in HMGB1-treated mice. Further, HMGB1-treated mice exhibited a ∼23% reduction in LV volume, a ∼48% increase in infarcted wall thickness and a ∼14% reduction in collagen deposition. HMGB1 induced cardiac regeneration and, within the infarcted region, it was found a ∼2-fold increase in c-kit⁺ cell number, a ∼13-fold increase in newly formed myocytes and a ∼2-fold increase in arteriole length density. HMGB1 also enhanced MMP2 and MMP9 activity and decreased TIMP-3 levels. Importantly, miR-206 expression 3 days after HMGB1 treatment was 4-5-fold higher than in control hearts and 20-25 fold higher that in sham operated hearts. HMGB1 ability to increase miR-206 was confirmed in vitro, in cardiac fibroblasts. TIMP3 was identified as a potential miR-206 target by TargetScan prediction analysis; further, in cultured cardiac fibroblasts, miR-206 gain- and loss-of-function studies and luciferase reporter assays showed that TIMP3 is a direct target of miR-206.
  
  
  CONCLUSIONS
  HMGB1 injected into chronically failing hearts enhanced LV function and attenuated LV remodelling; these effects were associated with cardiac regeneration, increased collagenolytic activity, miR-206 overexpression and miR-206 -mediated inhibition of TIMP-3.
authors: Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
authors: Federica
authors: F
authors: Limana
authors: Grazia
authors: G
authors: Esposito
authors: Daniela
authors: D
authors: D'Arcangelo
authors: Anna
authors: A
authors: Di Carlo
authors: Sveva
authors: S
authors: Romani
authors: Guido
authors: G
authors: Melillo
authors: Antonella
authors: A
authors: Mangoni
authors: Chiara
authors: C
authors: Bertolami
authors: Giulio
authors: G
authors: Pompilio
authors: Antonia
authors: A
authors: Germani
authors: Maurizio C
authors: MC
authors: Capogrossi
mesh_terms: D000818:Animals; D001483:Base Sequence; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D024243:HMGB1 Protein / Q000494:pharmacology*; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000150:complications / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology*; D006334:Heart Function Tests; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D012038:Regeneration / Q000187:drug effects* / Q000235:genetics; D016019:Survival Analysis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D024243:HMGB1 Protein; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D019717:Tissue Inhibitor of Metalloproteinase-3; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9