High Mobility Group Box 1 protein (HMGB1), also known as amphoterin, is a 215 amino acid molecule that is highly conserved throughout evolution and ubiquitously expressed in most cell types. It is predominantly a nuclear protein that is involved in stabilizing nucleosome structure and regulating the binding of transcription factors via two positively charged DNA-binding domains, Box A and Box B. HMGB1 also has important extracellular functions including a role as a potential biomarker upon release from cells. Two distinct mechanisms have been described for its release [
]: (1) passive release from necrotic cells following disruption of nuclear and cell membranes. This mechanism of release is necrosis specific, as apoptotic cells retain HMGB1. (2) Active secretion by innate immune cells (e.g. monocytes and macrophages) in response to and as an amplifier of proinflammatory signals. HMGB1 released from cells is highly proinflammatory via interactions with several receptors including the receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-2, -4, and -9 [
- Raucci A.
- Palumbo R.
- Bianchi M.E.
HMGB1: a signal of necrosis.
Autoimmunity. 2007; 40: 285-289
- Basta G.
Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications.
Atherosclerosis. 2008; 196: 9-21
3]. The pivotal biological role of HMGB1 is underlined by it functioning as an alarmin; it has important roles in recruiting and activating antigen-presenting cells (e.g. dendritic cells), enhancing both innate and adaptive immune responses, and acting as an endogenous danger signal, reporting cell damage/necrosis and the necessity of repair and inducing a “sterile” immune response [
- den Dekker W.K.
- Cheng C.
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- Duckers H.J.
Toll like receptor 4 in atherosclerosis and plaque destabilization.
Atherosclerosis. 2010; 209: 314-320
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- Dhpar R.
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- Billiar T.R.
- Tsung A.
HMGB1: endogenous danger signaling.
Mol Med. 2008; 14: 476-484
5]. These important functions of extracellular HMGB1 make it a highly attractive candidate as biomarker of cell ischemia and cell damage.
- Yang D.
- Tewary P.
- de la Rosa G.
- Wei F.
- Oppenheim J.J.
The alarmin functions of high-mobility group proteins.
Biochim Biophys Acta. 2010; 1799: 157-163
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- HMGB1: a signal of necrosis.Autoimmunity. 2007; 40: 285-289
- Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications.Atherosclerosis. 2008; 196: 9-21
- Toll like receptor 4 in atherosclerosis and plaque destabilization.Atherosclerosis. 2010; 209: 314-320
- HMGB1: endogenous danger signaling.Mol Med. 2008; 14: 476-484
- The alarmin functions of high-mobility group proteins.Biochim Biophys Acta. 2010; 1799: 157-163
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Published online: December 28, 2011
Accepted: November 30, 2011
Received: November 28, 2011
© 2011 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
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- Circulating high-mobility group box 1 and cardiovascular mortality in unstable angina and non-ST-segment elevation myocardial infarctionAtherosclerosisVol. 221Issue 2
- Preview► HMGB1 is a damage-associated molecular pattern molecule. ► We evaluated the prognostic value of HMGB1 on admission in 258 UA/NSTEMI patients. ► Increased HMGB1 was significantly associated with cardiovascular mortality rate. ► Increased HMGB1 was an independent predictor of cardiovascular mortality. ► Measurements of HMGB1 improve the early risk stratification of UA/NSTEMI patients.