Aims 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. Methods and 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.
|Titolo:||HMGB1 attenuates cardiac remodelling in the failing heart via enhanced cardiac regeneration and miR-206-mediated inhibition of TIMP-3|
|Parole Chiave:||Animals; MicroRNAs; Humans; HEK293 Cells; Matrix Metalloproteinase 2; Hemodynamics; Heart Function Tests; Fibroblasts; Collagen; Molecular Sequence Data; Gene Expression Regulation; Myocardial Infarction; Myocytes, Cardiac; Matrix Metalloproteinase 9; Myocardium; Survival Analysis; Heart; Ventricular Remodeling; Heart Failure; Mice; HMGB1 Protein; Base Sequence; Tissue Inhibitor of Metalloproteinase-3; Regeneration; Female|
|Settore Scientifico Disciplinare:||Settore MED/23 - Chirurgia Cardiaca|
|Data di pubblicazione:||2011|
|Digital Object Identifier (DOI):||10.1371/journal.pone.0019845|
|Appare nelle tipologie:||01 - Articolo su periodico|