Role of HMGB1 in cardiovascular diseases
Abstract
A nuclear protein, high mobility group box 1 (HMGB1), is released passively by necrotic cells, and actively by macrophages/monocytes in response to exogenous and endogenous inflammatory stimuli. After binding to the receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4), HMGB1 activates vascular endothelial cells and macrophages/monocytes to express proinflammatory cytokines, chemokines and adhesion molecules. Pharmacological suppression of its activities or release is protective against lethal endotoxemia and sepsis, establishing HMGB1 as a critical mediator of lethal systemic inflammation. In light of the pathogenic role of inflammation in cardiovascular diseases, we propose that HMGB1, a proinflammatory cytokine derived from both injured endothelium and activated macrophages/monocytes, could contribute to the progression of atherosclerosis and other cardiovascular diseases.
References and recommended reading
References
- 1. Wang H, Yang H, Tracey KJExtracellular role of HMGB1 in inflammation and sepsis. J Intern Med. 2004;255:320–331. The authors provide a detailed review of the extracellular role of HMGB1 in inflammation as well as lethal systemic inflammatory diseases such as endotoxemia and sepsis. [[PubMed][Google Scholar]
- 2. Chen G, Li J, Qiang X, Czura CJ, Ochani M, Ochani K, Ulloa L, Yang H, Tracey KJ, Wang P, et al Suppression of HMGB1 release by stearoyl lysophosphatidylcholine:an additional mechanism for its therapeutic effects in experimental sepsis. J Lipid Res. 2005;46:623–627.[PubMed][Google Scholar]
- 3. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi MEMonocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003;22:5551–5560.[Google Scholar]
- 4. Muller S, Ronfani L, Bianchi MERegulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J Intern Med. 2004;255:332–343. The authors provide an excellent review of the subcellular localization of HMGB1 in various types of cells, and discuss how HMGB1 translocation is tightly regulated at a molecular level. [[PubMed][Google Scholar]
- 5. Huttunen HJ, Rauvala HAmphoterin as an extracellular regulator of cell motility: from discovery to disease. J Intern Med. 2004;255:351–366. In this review, the authors present a detailed review of the role of amphoterin, a cytoplasmic membrane-bound form of HMGB1, in the regulation of cell migration using cell-surface receptors such as RAGE. [[PubMed][Google Scholar]
- 6. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, et al HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285:248–251.[PubMed][Google Scholar]
- 7. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, et al Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA. 2004;101:296–301.[Google Scholar]
- 8. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al Abed Y, Wang H, Metz C, Miller EJ, et al Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10:1216–1221.[PubMed][Google Scholar]
- 9. Wang H, Vishnubhakat JM, Bloom O, Zhang M, Ombrellino M, Sama A, Tracey KJProinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes. Surgery. 1999;126:389–392.[PubMed][Google Scholar]
- 10. Rendon-Mitchell B, Ochani M, Li J, Han J, Wang H, Yang H, Susarla S, Czura C, Mitchell RA, Chen G, et al IFN-gamma induces high mobility group box 1 protein release partly through a TNF-dependent mechanism. J Immunol. 2003;170:3890–3897.[PubMed][Google Scholar]
- 11. Chen G, Li J, Ochani M, Rendon-Mitchell B, Qiang X, Susarla S, Ulloa L, Yang H, Fan S, Goyert SM, et al Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms. J Leukoc Biol. 2004;76:994–1001.[PubMed][Google Scholar]
- 12. Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli AThe nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 2002;3:955–1001.[Google Scholar]
- 13. Scaffidi P, Misteli T, Bianchi MERelease of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191–195.[PubMed][Google Scholar]
- 14. Degryse B, Bonaldi T, Scaffidi P, Muller S, Resnati M, Sanvito F, Arrigoni G, Bianchi METhe high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol. 2001;152:1197–1206.[Google Scholar]
- 15. Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey KJ, Geller DA, Billiar TRThe nuclear factor HMGB1 mediates hepatic injury after murine liver ischemiareperfusion. J Exp Med. 2005;201:1135–1143.[Google Scholar]
- 16. Wang H, Yang H, Czura CJ, Sama AE, Tracey KJHMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med. 2001;164:1768–1773.[PubMed][Google Scholar]
- 17. Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, Lee ML, Andersson J, Tokics L, Treutiger CJPersistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med. 2005;33:564–573.[PubMed][Google Scholar]
- 18. Kim JY, Park JS, Strassheim D, Douglas I, Diaz V, Asehnoune K, Mitra S, Kwak SH, Yamada S, Maruyama I, et al HMGB1 contributes to the development of acute lung injury after hemorrhage. Am J Physiol Lung Cell Mol Physiol. 2005;288:L958–L965.[PubMed][Google Scholar]
- 19. Ombrellino M, Wang H, Ajemian MS, Talhouk A, Scher LA, Friedman SG, Tracey KJIncreased serum concentrations of high-mobility-group protein 1 in haemorrhagic shock [Letter] Lancet. 1999;354:1446–1447.[PubMed][Google Scholar]
- 20. Sappington PL, Yang R, Yang H, Tracey KJ, Delude RL, Fink MPHMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology. 2002;123:790–802.[PubMed][Google Scholar]
- 21. Kokkola R, Andersson A, Mullins G, Ostberg T, Treutiger CJ, Arnold B, Nawroth P, Andersson U, Harris RA, Harris HERAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand J Immunol. 2005;61:1–9.[PubMed][Google Scholar]
- 22. Huttunen HJ, Fages C, Kuja-Panula J, Ridley AJ, Rauvala HReceptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res. 2002;62:4805–4811.[PubMed][Google Scholar]
- 23. Messmer D, Yang H, Telusma G, Knoll F, Li J, Messmer B, Tracey KJ, Chiorazzi NHigh mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol. 2004;173:307–313.[PubMed][Google Scholar]
- 24. Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X, Harris HE, Czura CJ, Wang H, Ulloa L, et al Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med. 2003;9:37–45.[Google Scholar]
- 25. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham EInvolvement of TLR 2 and TLR 4 in cellular activation by high mobility group box 1 protein (HMGB1) J Biol Chem. 2003;279:7370–7377.[PubMed][Google Scholar]
- 26. Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY, Choe KH, Strassheim D, Pitts TM, Tracey KJ, Abraham EActivation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol. 2003;284:C870–C879.[PubMed][Google Scholar]
- 27. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, Suffredini AFInflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2003;101:2652–2660.[PubMed][Google Scholar]
- 28. Treutiger CJ, Mullins GE, Johansson AS, Rouhiainen A, Rauvala HM, Erlandsson-Harris H, Andersson U, Yang H, Tracey KJ, Andersson J, Palmblad JEHigh mobility group 1 B-box mediates activation of human endothelium. J Intern Med. 2003;254:375–385.[PubMed][Google Scholar]
- 29. Ueno H, Matsuda T, Hashimoto S, Amaya F, Kitamura Y, Tanaka M, Kobayashi A, Maruyama I, Yamada S, Hasegawa N, et al Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am J Respir Crit Care Med. 2004;170:1310–1316.[PubMed][Google Scholar]
- 30. Lin X, Yang H, Sakuragi T, Hu M, Mantell LL, Hayashi S, Al Abed Y, Tracey KJ, Ulloa L, Miller EJAlpha-chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis. Am J Physiol Lung Cell Mol Physiol. 2005;289:L583–L590.[PubMed][Google Scholar]
- 31. Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJHMG-1 as a mediator of acute lung inflammation. J Immunol. 2000;165:2950–2954.[PubMed][Google Scholar]
- 32. Agnello D, Wang H, Yang H, Tracey KJ, Ghezzi PHMGB1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. Cytokine. 2002;18:231–236.[PubMed][Google Scholar]
- 33. Chacur M, Milligan ED, Gazda LS, Armstrong C, Wang H, Tracey KJ, Maier SF, Watkins LRA new model of sciatic inflammatory neuritis (SIN): induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats. Pain. 2001;94:231–244.[PubMed][Google Scholar]
- 34. Sappington PL, Yang R, Yang H, Tracey KJ, Delude RL, Fink MPHMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and causes derangements in intestinal barrier function in mice. Gastroenterology. 2002;123:790–802.[PubMed][Google Scholar]
- 35. Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, Czura CJ, Fink MP, Tracey KJEthyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci USA. 2002;99:12351–12356.[Google Scholar]
- 36. Cui X, Wu R, Zhou M, Dong W, Ulloa L, Yang H, Wang H, Tracey KJ, Simms HH, Wang PAdrenomedullin and its binding protein attenuate the proinflammatory response after hemorrhage. Crit Care Med. 2005;33:391–398.[PubMed][Google Scholar]
- 37. Yan JJ, Jung JS, Lee JE, Lee J, Huh SO, Kim HS, Jung KC, Cho JY, Nam JS, Suh HW, et al Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nat Med. 2004;10:161–167.[PubMed][Google Scholar]
- 38. Wang H, Czura CJ, Tracey KJLipid unites disparate syndromes of sepsis. Nat Med. 2004;10:124–125.[PubMed][Google Scholar]
- 39. Yin K, Gribbin E, Wang HInterferon-gamma inhibition attenuates lethality after cecal ligation and puncture in rats: implication of high mobility group box 1. Shock. 2005;24:396–401.[PubMed][Google Scholar]
- 40. Chen X, Li W, Wang HMore tea for septic patients? - Green tea suppresses bacterial endotoxin-induced HMGB1 release. Med Hypotheses. 2006;66:660–663.[Google Scholar]
- 41. Wang H, Li W, Li J, Rendon-Mitchell B, Ochani M, Ashok M, Yang L, Tracey KJ, Wang P, Sama AEThe aqueous extract of a popular herbal nutrient supplement, Angelica sinensis, protects mice against lethal endotoxemia and sepsis. J Nutr. 2006;136:360–365.[Google Scholar]
- 42. Mehra VC, Ramgolam VS, Bender JRCytokines and cardiovascular disease. J Leukoc Biol. 2005;78:805–818.[PubMed][Google Scholar]
- 43. Paoletti R, Gotto AM, Jr, Hajjar DPInflammation in atherosclerosis and implications for therapy. Circulation. 2004;109:III20–III26.[PubMed][Google Scholar]
- 44. Kalinina N, Agrotis A, Antropova Y, DiVitto G, Kanellakis P, Kostolias G, Ilyinskaya O, Tararak E, Bobik AIncreased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions: role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol. 2004;24:2320–2325. This is the first article reporting that HMGB1 expression levels are upregulated in atherosclerotic lesions, providing the first evidence for a potential link between HMGB1 and atherosclerosis. [[PubMed][Google Scholar]
- 45. Mullins GE, Sunden-Cullberg J, Johansson AS, Rouhiainen A, Erlandsson-Harris H, Yang H, Tracey KJ, Rauvala H, Palmblad J, Andersson J, Treutiger CJActivation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scand J Immunol. 2004;60:566–573.[PubMed][Google Scholar]
- 46. Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, Uchimura T, Ida N, Yamazaki Y, Yamada S, et al The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest. 2005;115:1267–1274.[Google Scholar]
- 47. Laszik ZG, Zhou XJ, Ferrell GL, Silva FG, Esmon CTDown-regulation of endothelial expression of endothelial cell protein C receptor and thrombomodulin in coronary atherosclerosis. Am J Pathol. 2001;159:797–802.[Google Scholar]
- 48. Rouhiainen A, Imai S, Rauvala H, Parkkinen JOccurrence of amphoterin (HMG1) as an endogenous protein of human platelets that is exported to the cell surface upon platelet activation. Thromb Haemost. 2000;84:1087–1094.[PubMed][Google Scholar]
- 49. Hansson GKInflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–1695.[PubMed][Google Scholar]
- 50. Bradshaw G, Gutierrez A, Miyake JH, Davis KR, Li AC, Glass CK, Curtiss LK, Davis RAFacilitated replacement of Kupffer cells expressing a paraoxonase-1 transgene is essential for ameliorating atherosclerosis in mice. Proc Natl Acad Sci USA. 2005;102:11029–11034.[Google Scholar]
- 51. Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, De Cesare D, De Blasis G, Muraro R, Bei R, et al The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation. 2003;108:1070–1077.[PubMed][Google Scholar]
- 52. Park L, Raman KG, Lee KJ, Lu Y, Ferran LJ, Jr, Chow WS, Stern D, Schmidt AMSuppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med. 1998;4:1025–1031.[PubMed][Google Scholar]
- 53. Bucciarelli LG, Wendt T, Qu W, Lu Y, Lalla E, Rong LL, Goova MT, Moser B, Kislinger T, Lee DC, et al RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice. Circulation. 2002;106:2827–2835.[PubMed][Google Scholar]
- 54. Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OF, Espevik T, Sundan AInflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation. 2002;105:685–690.[PubMed][Google Scholar]
- 55. Woo YJ, Taylor MD, Cohen JE, Jayasankar V, Bish LT, Burdick J, Pirolli TJ, Berry MF, Hsu V, Grand TEthyl pyruvate preserves cardiac function and attenuates oxidative injury after prolonged myocardial ischemia. J Thorac Cardiovasc Surg. 2004;127:1262–1269.[PubMed][Google Scholar]
- 56. Cheng TOAll teas are not created equal – The Chinese green tea and cardiovascular health. Int J Cardiol. 2005 [Epub ahead of print] [[PubMed][Google Scholar]
- 57. Wang PAndrenomedullin and cardiovascular responses in sepsis. Peptides. 2001;22:1835–1840.[PubMed][Google Scholar]
- 58. Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A, Cossu G, Bianchi MEExtracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol. 2004;164:441–449. This is the first report suggesting that low levels of HMGB1 may be beneficial in tissue repair by attracting stem cells. [Google Scholar]
- 59. Limana F, Germani A, Zacheo A, Kajstura J, Di Carlo A, Borsellino G, Leoni O, Palumbo R, Battistini L, Rastaldo R, et al Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-Kit+ cell proliferation and differentiation. Circ Res. 2005;97:e73–e83.[PubMed][Google Scholar]

