title: Therapeutic potential of high mobility group box-1 in ischemic injury and tissue regeneration.
abstract: High-mobility group box-1 (HMGB1) is a nuclear protein that acts as a cytokine when released into the extracellular milieu by necrotic and inflammatory cells, and is involved in inflammatory responses and tissue repair. This protein is released passively during cellular necrosis by almost all cells that have a nucleus, but is also actively secreted by immune cells such as macrophages and monocytes. This cytokine plays a key role in mediating the local and systemic responses to several stimuli and might have therapeutic relevance. Indeed, vessel-associated stem cells, injected into the general circulation of dystrophic mice, migrate to sites of tissue damage in response to the HMGB1 signal, by a nuclear factor-κB  dependent mechanism. Moreover, endogenous HMGB1 enhances angiogenesis and restores cardiac function in a murine model of myocardial infarction, and the exogenous administration of HMGB1 after myocardial infarction leads to the recovery of left ventricular function through the regeneration of cardiomyocytes. Finally, recent findings show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent manner. The mechanisms of action of this protein are complex and are not well known or defined. The objective of this review is to evaluate the data regarding the tissue regeneration effects of HMGB1, with the aim of providing practical considerations about this topic for the management of subjects affected by ischemic and degenerative diseases.
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy. f.biscetti@gmail.com
authors.forename: Federico
authors.initials: F
authors.lastname: Biscetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ghirlanda
authors.forename: Andrea
authors.initials: A
authors.lastname: Flex
mesh_terms: D000818:Animals; D024243:HMGB1 Protein / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007511:Ischemia / Q000150:complications* / Q000473:pathology; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic; D012038:Regeneration / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D024243:HMGB1 Protein; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A