Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation.
High-mobility group box 1 protein (HMGB1) is a chromatin protein that is released by inflammatory and necrotic cells. Extracellular HMGB1 signals tissue damage, stimulates the secretion of proinflammatory cytokines and chemokines, and modulates stem cell function. The present study examined exogenous HMGB1 effect on mouse left-ventricular function and myocyte regeneration after infarction. Myocardial infarction was induced in C57BL/6 mice by permanent coronary artery ligation. After 4 hours animals were reoperated and 200 ng of purified HMGB1 was administered in the peri-infarcted left ventricle. This intervention resulted in the formation of new myocytes within the infarcted portion of the wall. The regenerative process involved the proliferation and differentiation of endogenous cardiac c-kit+ progenitor cells. Circulating c-kit+ cells did not significantly contribute to HMGB1-mediated cardiac regeneration. Echocardiographic and hemodynamic parameters at 1, 2, and 4 weeks demonstrated a significant recovery of cardiac performance in HMGB1-treated mice. These effects were not observed in infarcted hearts treated either with the unrelated protein glutathione S-transferase or a truncated form of HMGB1. Thus, HMGB1 appears to be a potent inducer of myocardial regeneration following myocardial infarction.
Limana
Federica
F
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Germani
Antonia
A
Zacheo
Antonella
A
Kajstura
Jan
J
Di Carlo
Anna
A
Borsellino
Giovanna
G
Leoni
Omar
O
Palumbo
Roberta
R
Battistini
Luca
L
Rastaldo
Raffaella
R
Müller
Susanne
S
Pompilio
Giulio
G
Anversa
Piero
P
Bianchi
Marco E
ME
Capogrossi
Maurizio C
MC
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018031:Connexin 43 / Q000032:analysis; D024243:HMGB1 Protein / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis*; D012038:Regeneration / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D018031:Connexin 43; D024243:HMGB1 Protein; D019009:Proto-Oncogene Proteins c-kit