HMGB1 attenuates cardiac remodelling in the failing heart via enhanced cardiac regeneration and miR-206-mediated inhibition of TIMP-3

Federica Limana, Grazia Esposito, Daniela D'Arcangelo, Anna Di Carlo, Sveva Romani, Guido Melillo, Antonella Mangoni, Chiara Bertolami, Giulio Pompilio, Antonia Germani, Maurizio C. Capogrossi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere19845
JournalPLoS One
Volume6
Issue number6
DOIs
Publication statusPublished - 2011

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Tissue Inhibitor of Metalloproteinase-3
HMGB1 Protein
Regeneration
heart
mice
fibroblasts
Left Ventricular Function
Fibroblasts
myocardial infarction
echocardiography
coronary vessels
luciferase
hemodynamics
myocytes
collagen
Echocardiography
injection
Ventricular Remodeling
Hemodynamics
prediction

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

HMGB1 attenuates cardiac remodelling in the failing heart via enhanced cardiac regeneration and miR-206-mediated inhibition of TIMP-3. / Limana, Federica; Esposito, Grazia; D'Arcangelo, Daniela; Di Carlo, Anna; Romani, Sveva; Melillo, Guido; Mangoni, Antonella; Bertolami, Chiara; Pompilio, Giulio; Germani, Antonia; Capogrossi, Maurizio C.

In: PLoS One, Vol. 6, No. 6, e19845, 2011.

Research output: Contribution to journalArticle

Limana, Federica ; Esposito, Grazia ; D'Arcangelo, Daniela ; Di Carlo, Anna ; Romani, Sveva ; Melillo, Guido ; Mangoni, Antonella ; Bertolami, Chiara ; Pompilio, Giulio ; Germani, Antonia ; Capogrossi, Maurizio C. / HMGB1 attenuates cardiac remodelling in the failing heart via enhanced cardiac regeneration and miR-206-mediated inhibition of TIMP-3. In: PLoS One. 2011 ; Vol. 6, No. 6.
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abstract = "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.",
author = "Federica Limana and Grazia Esposito and Daniela D'Arcangelo and {Di Carlo}, Anna and Sveva Romani and Guido Melillo and Antonella Mangoni and Chiara Bertolami and Giulio Pompilio and Antonia Germani and Capogrossi, {Maurizio C.}",
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T1 - HMGB1 attenuates cardiac remodelling in the failing heart via enhanced cardiac regeneration and miR-206-mediated inhibition of TIMP-3

AU - Limana, Federica

AU - Esposito, Grazia

AU - D'Arcangelo, Daniela

AU - Di Carlo, Anna

AU - Romani, Sveva

AU - Melillo, Guido

AU - Mangoni, Antonella

AU - Bertolami, Chiara

AU - Pompilio, Giulio

AU - Germani, Antonia

AU - Capogrossi, Maurizio C.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

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