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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2017

Open Access 01-12-2017 | Original investigation

Serum high mobility group box-1 and osteoprotegerin levels are associated with peripheral arterial disease and critical limb ischemia in type 2 diabetic subjects

Authors: Silvia Giovannini, Giovanni Tinelli, Federico Biscetti, Giuseppe Straface, Flavia Angelini, Dario Pitocco, Luciana Mucci, Raffaele Landolfi, Andrea Flex

Published in: Cardiovascular Diabetology | Issue 1/2017

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Abstract

Background

High mobility group box-1 (HMGB-1) is a nuclear protein also acting as inflammatory mediator, whilst osteoprotegerin (OPG), member of tumor necrosis factor receptor superfamily, is indicated as marker of vascular calcification. Peripheral artery disease (PAD) and type 2 diabetes (T2D) are clinical conditions characterized by elevated serum inflammatory markers and vascular calcification enhancement. The aim of this study was to investigate the potential role of HMGB-1, OPG and several inflammatory mediators such as C-reactive protein (HsCRP), tumor necrosis factor-alpha and interleukin-6 (IL-6) on the presence and severity of peripheral artery disease in patients with T2D.

Methods

In this retrospective observational study, we have analyzed HMGB-1, OPG and inflammatory cytokines serum levels in 1393 type 2 diabetic patients with PAD and without PAD (WPAD).

Results

HMGB-1 (7.89 ± 15.23 ng/mL), OPG (6.54 ± 7.76 pmol/L), HsCRP (15.6 ± 14.4 mg/L) and IL-6 (56.1 ± 28.6 pg/mL) serum levels were significantly higher in patients with PAD than in those WPAD (3.02 ± 8.12 ng/mL, P ˂ 0.001; 2.98 ± 2.01 pmol/L, P < 0.001; 7.05 ± 4.4 mg/L, P < 0.001; 37.5 ± 20.2 pg/mL, P < 0.001 respectively). Moreover HMGB-1 (P < 0.001), OPG (P < 0.001), HsCRP (P < 0.001) and IL-6 (P < 0.001) serum levels were positively correlated with clinical severity of PAD. HMGB-1 (adjusted OR 12.32; 95% CI 3.56–23.54, P = 0.023) and OPG (adjusted OR 3.53; 95% CI 1.54–6.15, P = 0.019) resulted independent determinants of PAD in patients with T2D after adjusting for the conventional cardiovascular risk factor and established inflammatory mediators.

Conclusions

In T2D patients HMGB-1 and OPG serum levels are higher in patients affected by PAD and independently associated with its occurrence and clinical severity.
Literature
1.
Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, Krook SH, Hunninghake DB, Comerota AJ, Walsh ME, McDermott MM, Hiatt WR. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286(11):1317–24.CrossRefPubMed
2.
3.
Tousoulis DL, Kampoli AM, Stefanadis C. Diabetes mellitus and vascular endothelial dysfunction: current perspectives. Curr Vasc Pharmacol. 2012;10(1):19–32.CrossRefPubMed
4.
Tousoulis DL, Papageorgiou N, Androulakis E, Siasos G, Latsios G, Tentolouris K, Stefanadis C. Diabetes mellitus-associated vascular impairment: novel circulating biomarkers and therapeutic approaches. J Am Coll Cardiol. 2013;62(8):667–76.CrossRefPubMed
5.
Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191–5.CrossRefPubMed
6.
Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, Suffredini AF. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2003;101(7):2652–60.CrossRefPubMed
7.
Mai J, Virtue A, Shen J, Wang H, Yang XF. An evolving new paradigm: endothelial cells–conditional innate immune cells. J Hematol Oncol. 2013;22(6):61.CrossRef
8.
Kawahara K, Biswas KK, Unoshima M, Ito T, Kikuchi K, Morimoto Y, Iwata M, Tancharoen S, Oyama Y, Takenouchi K, et al. C-reactive protein induces high mobility group box-1 protein release through activation of p38MAPK in macrophage RAW264 7 cells. Cardiovasc Pathol. 2008;17(3):129–38.CrossRefPubMed
9.
Erlandsson Harris H, Andersson U. Mini-review: the nuclear protein HMGB-1 as a proinflammatory mediator. Eur J Immunol. 2004;34(6):1503–12.CrossRefPubMed
10.
Nogueira-Machado JA, Volpe CMDO, Veloso CA, Chaves MM. HMGB1, TLR and RAGE: a functional tripod that leads to diabetic inflammation. Expert Opin Ther Targets. 2011;15(8):1023–35.CrossRefPubMed
11.
Zhao Z, Wang Y, Tang K, Xu Y. Increased serum HMGB1 related with HbA1c in coronary artery disease in type 2 diabetes mellitus. Int J Cardiol. 2013;168(2):1559–60.CrossRefPubMed
12.
Pachydaki SI, Tari SR, Lee SE, Ma W, Tseng JJ, Sosunov AA, Cataldergirmen G, Scarmeas N, Caspersen C, Chang S, et al. Upregulation of RAGE and its ligands in proliferative retinal disease. Exp Eye Res. 2006;82(5):807–15.CrossRefPubMed
13.
Kim J, Sohn E, Kim C-S, Jo K, Kim JS. The role of high mobility group box-1 protein in the development of diabetic nephropathy. Am J Nephrol. 2011;33(6):524–9.CrossRefPubMed
14.
Skrha J Jr, Kalousova M, Svarcová J, Muravska A, Kvasnička J, Landová L, Zima T, Slrha J. Relationship of soluble RAGE and RAGE ligands HMGB1 and EN-RAGE to endothelial dysfunction in type 1 and type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2012;120(05):277–81.CrossRefPubMed
15.
Yang J, Shah R, Robling AG, Templeton E, Yang H, Tracey KJ, Bidwell JP. HMGB1 is a bone-active cytokine. J Cell Physiol. 2008;214(3):730–9.CrossRefPubMed
16.
Ziegler S, Kudlacek S, Luger A, Minar E. Osteoprotegerin plasma concentrations correlate with severity of peripheral artery disease. Atherosclerosis. 2005;182(1):175–80.CrossRefPubMed
17.
Kim J, Song TJ, Yang SH, Lee OH, Nam HS, Kim YD, Kim EH, Lee HS, Nam CM, Heo JH. Plasma osteoprotegerin levels increase with the severity of cerebral artery atherosclerosis. Clin Biochem. 2013;46(12):1036–40.CrossRefPubMed
18.
Harper E, Forde H, Davenport C, Rochfort KD, Smith D, Cummins PM. Vascular calcification in type-2 diabetes and cardiovascular disease: integrative roles for OPG, RANK, TRAIL. Vasc Pharmacol. 2016;82:30–40.CrossRef
19.
Kapetanios D, Karkos C, Giagtzidis I, Papazoglou K, Kiroplastis K, Spyridis C. Vascular calcification biomarkers and peripheral arterial disease. Int Angiol. 2016;35(5):455–9.PubMed
20.
Koshikawa M, Aizawa K, Kasai H, Izawa A, Tomita T, Kuzamaki S, Tsutsui H, Koyama J, Shimodaira S, Takahashi M, et al. Elevated osteopontin levels in patients with peripheral arterial disease. Angiology. 2009;60(1):42–5.CrossRefPubMed
21.
Pennisi P, Signorelli SS, Riccobene S, Celotta G, Di Pino L, La Malfa T, Fiore CE. Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels. Osteoporos Int. 2004;15(5):389–95.CrossRefPubMed
22.
Knudseb ST, Foss CH, Poulsen PL, Andersen NH, Mogensen CE, Rasmussen LM. Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications. Eur J Endocrinol. 2003;149(1):39–42.CrossRef
23.
Xiang GD, Xu L, Zhao LS, Yue L, Hou J. The relationship between plasma osteoprotegerin and endothelium-dependent arterial dilation in type 2 diabetes. Diabetes. 2006;55(7):2126–31.CrossRefPubMed
24.
Biscetti F, Straface G, Pitocco D, Angelini F, Tinelli G, Landolfi R, Flex A. Fibroblast growth factor 23 serum level in type 2 diabetic italian subjects with peripheral arterial disease and critical limb ischemia. Eur Rev Med Pharmacol Sci. 2016;20(19):4048–54.PubMed
25.
Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clément D, Collet JP, Cremonesi A, De Carlo M, Erbel R, Fowkes FG, et al. ESC guidelines on the diagnosis and treatment of peripheral artery diseases: document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the task force on the diagnosis and treatment of peripheral artery diseases of the european society of cardiology (ESC). Eur Heart J. 2011;32(22):2851–906.CrossRefPubMed
26.
Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FG, Hamburg NM, Kinlay S, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;69(11):e71–126.CrossRefPubMed
27.
Rutherford RB, Flanigan DP, Gupta SK, The Ad Hoc Committee on Reporting Standards SVS/ISCVS. Suggested standards for reports dealing with lower extremity ischaemia. J Vasc Surg. 1986;4(1):80–94.CrossRef
28.
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, TASC II Working Group. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45:S5–67.CrossRefPubMed
29.
Oozawa S, Sano S, Nishibori M. Usefulness of high mobility group box 1 protein as a plasma biomarker in patient with peripheral artery disease. Acta Med Okayama. 2014;68(3):157–62.PubMed
30.
Wyss TR, Adam L, Haynes AG, Kucher N, Silbernagel G, Do DD, Schmidli J, Baumgartner I. Impact of cardiovascular risk factors on severity of peripheral artery disease. Atherosclerosis. 2015;242(1):97–101.CrossRefPubMed
31.
Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 2000;192(4):565–70.CrossRefPubMedPubMedCentral
32.
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(5425):248–51.CrossRefPubMed
33.
Kalinina N, Agrotis A, Antropova Y, DiVitto G, Kanellakis P, Kostolias G, Ilyinskaya O, Tararak E, Bobik A. Increased expression of the DNA binding cytokine HMGB1 in human atherosclerotic lesions: role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol. 2004;24(12):2320–5.CrossRefPubMed
34.
35.
Malmstedt J, Kärvestedt L, Swedenborg J, Brismar K. The receptor for advanced glycation end products and risk of peripheral arterial disease, amputation or death in type 2 diabetes: a population-based cohort study. Cardiovasc Diabetol. 2015;14:93.CrossRefPubMedPubMedCentral
36.
Krishna SM, Moxon JV, Golledge J. A review of the pathophysiology and potential biomarkers for peripheral artery disease. Int J Mol Sci. 2015;16(5):11294–322.CrossRefPubMedPubMedCentral
37.
Porto A, Palumbo R, Pieroni M, Aprigliano G, Chiesa R, Sanvito F, Maseri A, Bianchi ME. Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box 1 protein. FASEB J. 2006;20(14):2565–6.CrossRefPubMed
38.
Brevetti G, Piscione F, Silvestro A, Galasso G, Di Donato A, Oliva G, Scopacasa F, Chiariello M. Increased inflammatory status and higher prevalence of three-vessel coronary artery disease in patients with concomitant coronary and peripheral atherosclerosis. Thromb Haemost. 2003;89(6):1058–63.PubMed
39.
Unlü Y, Karapolat S, Karaca Y, Kiziltunç A. Comparison of levels of inflammatory markers and hemostatic factors in the patients with and without peripheral arterial disease. Thromb Res. 2006;117(4):357–64.CrossRefPubMed
40.
Kanellakis P, Agrotis A, Kyaw TS, Koulis C, Ahrens I, Mori S, Takahashi HK, Liu K, Peter K, Nishibori M, et al. High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol. 2011;31(2):313–9.CrossRefPubMed
41.
Yan XX, Lu L, Peng WH, Wang LJ, Zhang Q, Zhang RY, Chen QJ, Shen WF. Increased serum HMGB1 level is associated with coronary artery disease in non diabetic and type 2 diabetic patients. Atherosclerosis. 2009;205(2):544–8.CrossRefPubMed
42.
Hu X, Jiang H, Bai Q, Zhou X, Xu C, Lu Z, Cui B, Wen H. Increased serum HMGB1 is related to the severity of coronary artery stenosis. Clin Chim Acta. 2009;406(1–2):139–42.CrossRefPubMed
43.
Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, Santer P, Smolen J, Poewe W, Willeit J. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004;109(18):2175–80.CrossRefPubMed
44.
Morisawa T, Nakagomi A, Kohashi K, Kosugi M, Kusama Y, Atarashi H, Shimizu W. Osteoprotegerin is associated with endothelial function and predicts early carotid atherosclerosis in patients with coronary artery disease. Int Heart J. 2015;56(6):605–12.CrossRefPubMed
45.
Esteghamati A, Aflatoonian M, Rad MV, Mazaheri T, Mousavizadeh M, Nakhjavani M, Noshad S. Association of osteoprotegerin with peripheral artery disease in patients with type 2 diabetes. Arch Cardiovasc Dis. 2015;108(8–9):412–9.CrossRefPubMed
46.
Niu Y, Zhang W, Yang Z, Li X, Wen J, Wang S, Zhang H, Wang X, Zhou H, Fang W, et al. Association of plasma osteoprotegerin levels with the severity of lower extremity arterial disease in patients with type 2 diabetes. BMC Cardiovasc Disord. 2015;15:86.CrossRefPubMedPubMedCentral
47.
Biscetti F, Straface G, Porreca CF, Bertoletti G, Vincenzoni C, Snider F, Stigliano E, Arena V, Angelini F, Pecorini G, et al. Increased FGF23 serum level is associated with unstable carotid plaque in type 2 diabetic subjects with internal carotid stenosis. Cardiovasc Diabetol. 2015;14:139.CrossRefPubMedPubMedCentral
48.
Zhang X, Hu Y, Zeng H, Li L, Zhao J, Zhao J, Liu F, Bao Y, Jia W. Serum fibroblast growth factor 21 levels is associated with lower extremity atherosclerotic disease in Chinese female diabetic patients. Cardiovasc Diabetol. 2015;14:32.CrossRefPubMedPubMedCentral
49.
Nagy EE, Varga-Fekete T, Puskas A, Kelemen P, Brassai Z, Szekeres-Csiki K, Gombos T, Csanyi MC, Harsfalvi J. High circulating osteoprotegerin levels are associated with non-zero blood groups. BMC Cardiovasc Disord. 2016;16(1):106.CrossRefPubMedPubMedCentral
50.
Min HL, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med. 2000;192(4):463–74.CrossRefPubMedPubMedCentral
51.
Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res. 2004;95(11):1046–57.CrossRefPubMed
52.
Pritzker LB, Scatena M, Giachelli CM. The role of osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand in human microvascular endothelial cell survival. Mol Biol Cell. 2004;15(6):2834–41.CrossRefPubMedPubMedCentral
53.
Zauli G, Corallini F, Bossi F, Fischetti F, Durigutto P, Celeghini C, Tedesco F, Secchiero P. Osteoprotegerin increases leukocyte adhesion to endothelial cells both in vitro and in vivo. Blood. 2007;110(2):536–43.CrossRefPubMed
54.
Secchiero PL, Corallini F, Pandolfi A, Consoli A, Candido R, Fabris B, Celeghini C, Capitani S, Zauli G. An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction. Am J Pathol. 2006;169(6):2236–44.CrossRefPubMedPubMedCentral
Metadata
Title
Serum high mobility group box-1 and osteoprotegerin levels are associated with peripheral arterial disease and critical limb ischemia in type 2 diabetic subjects
Authors
Silvia Giovannini
Giovanni Tinelli
Federico Biscetti
Giuseppe Straface
Flavia Angelini
Dario Pitocco
Luciana Mucci
Raffaele Landolfi
Andrea Flex
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2017
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-017-0581-z

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