High-Mobility Group Box 1 Protein in Myocardial Infarction: Should it be Stimulated or Inhibited?

High-mobility group box 1 (HMGB1) protein was originally identified as a non-histone nuclear protein that stabilizes the nucleosome structure and regulates gene transcription 1). HMGB1 is highly conserved and ubiquitously expressed in the nucleus of almost all mammalian cells. In 1999, Wang et al. 2) reported that HMGB1 is released from activated macrophages, and extracellular HMGB1 acts as a late and critical mediator of inflammatory responses in sepsis. This discovery has apparently stimulated further work on the inflam-matory role of extracellular HMGB1 in the patho-physiology of various diseases. Therefore, it is currently accepted that HMGB1 is a danger signal (i.e., alarmin or damage/danger-associated molecular pattern molecule), serving as a link between cellular damage and inflammation 3). Furthermore, it has been shown that HMGB1 is not only passively released from damaged cells but also actively secreted from stimulated cells, and it stimulates the induction of inflammatory cytokines and chemokines by interacting with its receptors, such as Toll-like receptors (TLR) and receptor for advanced glycation end products (RAGE). Increasing evidence indicates the importance of extracellular HMGB1 in the pathophysiology of myo-cardial infarction (MI). Previously, Kitahara et al. 4) developed a transgenic mouse model with cardiac over-expression of HMGB1 under the control of the α-cardiac myosin heavy chain promoter (αMHC/HMGB1-Tg mice) and showed that the plasma HMGB1 levels after MI were higher and the infarct size was smaller in the αMHC/HMGB1-Tg mice than in the wild-type (WT) mice. In addition, the αMHC/HMGB1-Tg mice showed enhanced angiogenesis in the MI border zone. Consistent with this, Kohno et al. 5) reported that HMGB1 inhibition by neutralizing antibody aggravated post-infarction healing process and remod-eling in a rat model of MI. In addition, it was reported that HMGB1 could contribute to the pathophysiol-ogy of MI through another mechanism. Limana et al. 6) demonstrated that when administered into the mouse heart, HMGB1 enhanced myocardial regenera-tion and differentiation of endogenous cardiac stem cells after MI, thereby resulting in improved cardiac dysfunction and remodeling. In the current issue of Journal of Atherosclerosis and Thrombosis, Nakamura et al. 7) , the same group of the study by Kitahara et al. 4) , studied the mechanism of how angiogenesis can be enhanced after MI in αMHC/HMGB1-Tg mice and found the contribution of bone marrow-derived endo-thelial progenitor cells (EPCs) in the enhanced angio-genesis. The authors used the αMHC/HMGB1-Tg mice whose bone marrow was replaced with that of green fluorescent protein (GFP) mice and …