The Role of HMGB1/RAGE in Inflammatory Cardiomyopathy

ABSTRACT

Heart failure is an increasingly prevalent disorder with considerable morbidity and mortality. Although many causal mechanisms such as inherited cardiomyopathies, ischemic cardiomyopathy, or muscular overload are easily identified in clinical practice, the events that determine the progression of cardiac injury to heart failure and adverse ventricular remodeling are still unclear. Yet there is compelling evidence that inflammatory mechanisms contribute to the progression of heart failure. High-mobility group box-1 (HMGB1) is a newly recognized potent innate “danger signal” that is released by necrotic cells and by activated immune cells. HMGB1 signals via the receptor for advanced glycation end-product (RAGE) and members of the toll-like receptor (TLR) family. We have demonstrated an important role for HMGB1 and RAGE in the pathogenesis of early- and late-phase complications following ischemia/reperfusion (I/R) injury of the heart. In addition, enhanced postmyocardial infarction remodeling in type 1 diabetes mellitus was partially mediated by HMGB1 activation. We propose that the interaction of HMGB1 and RAGE is a key component initiating and sustaining the inflammatory response in inflammatory cardiomyopathy eventually leading to heart failure. Thus HMGB1-antagonizing gene therapy represents a new therapeutic strategy.

HMGB1 - inflammation - innate immunity - inflammatory cardiomyopathy

REFERENCES

• 1 Alla F, Zannad F, Filippatos G. Epidemiology of acute heart failure syndromes.  Heart Fail Rev. 2007;  12(2) 91-95
• 2 Schocken D D, Benjamin E J, Fonarow G C American Heart Association Council on Epidemiology and Prevention et al. Prevention of heart failure: a scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group.  Circulation. 2008;  117(19) 2544-2565
• 3 Rauchhaus M, Doehner W, Francis D P et al.. Plasma cytokine parameters and mortality in patients with chronic heart failure.  Circulation. 2000;  102(25) 3060-3067
• 4 Deswal A, Petersen N J, Feldman A M, Young J B, White B G, Mann D L. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST).  Circulation. 2001;  103(16) 2055-2059
• 5 Kandolf R. Myocarditis and cardiomyopathy [in German].  Verh Dtsch Ges Pathol. 1996;  80 127-138
• 6 Pisani B, Taylor D O, Mason J W. Inflammatory myocardial diseases and cardiomyopathies.  Am J Med. 1997;  102(5) 459-469
• 7 Feldman A M, McNamara D. Myocarditis.  N Engl J Med. 2000;  343(19) 1388-1398
• 8 Kindermann I, Kindermann M, Kandolf R et al.. Predictors of outcome in patients with suspected myocarditis.  Circulation. 2008;  118(6) 639-648
• 9 D'Ambrosio A, Patti G, Manzoli A et al.. The fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: a review.  Heart. 2001;  85(5) 499-504
• 10 Richardson P, McKenna W, Bristow M et al.. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies.  Circulation. 1996;  93(5) 841-842
• 11 Codd M B, Sugrue D D, Gersh B J, Melton III L J. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984.  Circulation. 1989;  80(3) 564-572
• 12 Cowie M R, Mosterd A, Wood D A et al.. The epidemiology of heart failure.  Eur Heart J. 1997;  18(2) 208-225
• 13 Smith S C, Allen P M. Myosin-induced acute myocarditis is a T cell-mediated disease.  J Immunol. 1991;  147(7) 2141-2147
• 14 Liao L, Sindhwani R, Rojkind M, Factor S, Leinwand L, Diamond B. Antibody-mediated autoimmune myocarditis depends on genetically determined target organ sensitivity.  J Exp Med. 1995;  181(3) 1123-1131
• 15 Huber S A, Lodge P A. Coxsackievirus B-3 myocarditis. Identification of different pathogenic mechanisms in DBA/2 and Balb/c mice.  Am J Pathol. 1986;  122(2) 284-291
• 16 Kaya Z, Afanasyeva M, Wang Y et al.. Contribution of the innate immune system to autoimmune myocarditis: a role for complement.  Nat Immunol. 2001;  2(8) 739-745
• 17 Park J S, Arcaroli J, Yum H K et al.. Activation of gene expression in human neutrophils by high mobility group box 1 protein.  Am J Physiol Cell Physiol. 2003;  284(4) C870-C879
• 18 Scaffidi P, Misteli T, Bianchi M E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.  Nature. 2002;  418(6894) 191-195
• 19 Wang H, Bloom O, Zhang M et al.. HMG-1 as a late mediator of endotoxin lethality in mice.  Science. 1999;  285(5425) 248-251
• 20 Andersson U, Wang H, Palmblad K et al.. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes.  J Exp Med. 2000;  192(4) 565-570
• 21 Treutiger C J, Mullins G E, Johansson A S et al.. High mobility group 1 B-box mediates activation of human endothelium.  J Intern Med. 2003;  254(4) 375-385
• 22 Rovere-Querini P, Capobianco A, Scaffidi P et al.. HMGB1 is an endogenous immune adjuvant released by necrotic cells.  EMBO Rep. 2004;  5(8) 825-830
• 23 Yang H, Ochani M, Li J et al.. Reversing established sepsis with antagonists of endogenous high-mobility group box 1.  Proc Natl Acad Sci U S A. 2004;  101(1) 296-301
• 24 Andrassy M, Volz H C, Igwe J C et al.. High-mobility group box-1 in ischemia-reperfusion injury of the heart.  Circulation. 2008;  117(25) 3216-3226
• 25 Kokkola R, Sundberg E, Ulfgren A K et al.. High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis.  Arthritis Rheum. 2002;  46(10) 2598-2603
• 26 Ulfgren A K, Grundtman C, Borg K et al.. Down-regulation of the aberrant expression of the inflammation mediator high mobility group box chromosomal protein 1 in muscle tissue of patients with polymyositis and dermatomyositis treated with corticosteroids.  Arthritis Rheum. 2004;  50(5) 1586-1594
• 27 Park L, Raman K G, Lee K J et al.. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts.  Nat Med. 1998;  4(9) 1025-1031
• 28 Bierhaus A, Haslbeck K M, Humpert P M et al.. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily.  J Clin Invest. 2004;  114(12) 1741-1751
• 29 Haslbeck K M, Bierhaus A, Erwin S et al.. Receptor for advanced glycation endproduct (RAGE)-mediated nuclear factor-kappaB activation in vasculitic neuropathy.  Muscle Nerve. 2004;  29(6) 853-860
• 30 Haslbeck K M, Friess U, Schleicher E D et al.. The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy.  Acta Neuropathol. 2005;  110(3) 247-254
• 31 Sakaguchi T, Yan S F, Yan S D et al.. Central role of RAGE-dependent neointimal expansion in arterial restenosis.  J Clin Invest. 2003;  111(7) 959-972
• 32 Andrassy M, Igwe J, Autschbach F et al.. Posttranslationally modified proteins as mediators of sustained intestinal inflammation.  Am J Pathol. 2006;  169(4) 1223-1237
• 33 Yan S F, Ramasamy R, Naka Y, Schmidt A M. Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond.  Circ Res. 2003;  93(12) 1159-1169
• 34 Hori O, Brett J, Slattery T et al.. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system.  J Biol Chem. 1995;  270(43) 25752-25761
• 35 Kokkola R, Andersson A, Mullins G et al.. RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages.  Scand J Immunol. 2005;  61(1) 1-9
• 36 Yang D, Chen Q, Yang H, Tracey K J, Bustin M, Oppenheim J J. High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin.  J Leukoc Biol. 2007;  81(1) 59-66
• 37 Dumitriu I E, Baruah P, Valentinis B et al.. Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products.  J Immunol. 2005;  174(12) 7506-7515
• 38 Jaulmes A, Thierry S, Janvier B, Raymondjean M, Maréchal V. Activation of sPLA2-IIA and PGE2 production by high mobility group protein B1 in vascular smooth muscle cells sensitized by IL-1beta.  FASEB J. 2006;  20(10) 1727-1729
• 39 Fiuza C, Bustin M, Talwar S et al.. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells.  Blood. 2003;  101(7) 2652-2660
• 40 Mitola S, Belleri M, Urbinati C et al.. Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine.  J Immunol. 2006;  176(1) 12-15
• 41 Huttunen H J, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways.  J Biol Chem. 1999;  274(28) 19919-19924
• 42 Bierhaus A, Schiekofer S, Schwaninger M et al.. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.  Diabetes. 2001;  50(12) 2792-2808
• 43 Li J, Schmidt A M. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products.  J Biol Chem. 1997;  272(26) 16498-16506
• 44 Harja E, Bu D X, Hudson B I et al.. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice.  J Clin Invest. 2008;  118(1) 183-194
• 45 Göser S, Andrassy M, Buss S J et al.. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium.  Circulation. 2006;  114(16) 1693-1702
• 46 Liang Y, Zhou Y, Shen P. NF-kappaB and its regulation on the immune system.  Cell Mol Immunol. 2004;  1(5) 343-350