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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2377.)
© 2007 American Heart Association, Inc.

Vascular Biology

Multiple Effects of High Mobility Group Box Protein 1 in Skeletal Muscle Regeneration

Roberta De Mori; Stefania Straino; Anna Di Carlo; Antonella Mangoni; Giulio Pompilio; Roberta Palumbo; Marco E. Bianchi; Maurizio C. Capogrossi; Antonia Germani

From the Laboratorio di Patologia Vascolare (R.D.M., S.S., A.D.C., A.M., M.C.C.), Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy; Laboratorio di Biologia Vascolare e Terapia Genica (G.P., A.G.), Centro Cardiologico "I. Monzino", Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy; the Department of Molecular Biology and Functional Genomics (R.P.), San Raffaele Research Institute Milano, Italy. San Raffaele University (M.E.B.), Milano, Italy; Fondazione "Livio Patrizi" (A.G.), Laboratori di Ricerca Gruppo BIOS, Roma, Italy.

Correspondence to Antonia Germani, PhD, Centro Cardiologico Monzino, Via Parea 420138 Milano, Italy. E-mail a.germani{at}idi.it

Objective— High mobility group box 1 protein (HMGB1) is a cytokine released by necrotic and inflammatory cells in response to injury. We examined the role of HMGB1 in skeletal muscle regeneration after hindlimb ischemia.

Methods and Results— Unilateral hindlimb ischemia was induced in mice by femoral artery dissection. HMGB1 levels increased in regenerating skeletal muscle and the blockade of endogenous HMGB1 by the administration of its truncated form, the BoxA, resulted in the reduction of vessel density. In contrast, intramuscular administration of HMGB1 enhanced perfusion and increased the number of regenerating fibers. To separately study the myogenic and the angiogenic effects of HMGB1, in vitro experiments were performed with isolated myoblasts and endothelial cells. Myoblasts were found to express the HMGB1 receptor RAGE and TLR4 which were downregulated during in vitro myogenic differentiation. HMGB1 was extracellularly released by differentiated myoblasts and exerted a chemotactic activity on myogenic cells. This effect was partially dependent on RAGE and was inhibited by BoxA treatment. Finally, HMGB1 stimulated tubular-like structure formation by endothelial cells through the activation of extracellular signal-regulated kinase (ERK) and JNK signal transduction pathways.

Conclusions— HMGB1 plays a role in skeletal muscle regeneration modulating, in an autocrine-paracrine manner, myoblast and endothelial cell functions.

In this study we provide evidence of the involvement of HMGB1 in skeletal muscle regeneration. Endogenous HMGB1 blockade or HMGB1 administration, in a mouse model of hindlimb ischemia, affect myoblast function and neovascularization. HMGB1 induces myoblast migration and modulates endothelial cell functions in vitro, activating JNK and ERK signaling pathways.

Key Words: hindlimb ischemia • HMGB1 • cytokines • regeneration