Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Letter Article

Osteoprotegerin and Osteopontin Serum Levels are Associated with Vascular Function and Inflammation in Coronary Artery Disease Patients

Author(s): Konstantinos Maniatis, Gerasimos Siasos*, Evangelos Oikonomou, Manolis Vavuranakis, Marina Zaromytidou, Konstantinos Mourouzis, Thodoros Paraskevopoulos, Georgios Charalambous, Athanasios G. Papavassiliou and Dimitris Tousoulis

Volume 18, Issue 5, 2020

Page: [523 - 530] Pages: 8

DOI: 10.2174/1570161117666191022095246

Price: $65

conference banner
Abstract

Background: Osteoprotegerin and osteopontin have recently emerged as key factors in both vascular remodelling and atherosclerosis progression. Interleukin-6 (IL-6) is an inflammatory cytokine with a key role in atherosclerosis. The relationship of osteoprotegerin, osteopontin, and IL-6 serum levels with endothelial function and arterial stiffness was evaluated in patients with coronary artery disease (CAD).

Methods: We enrolled 219 patients with stable CAD and 112 control subjects. Osteoprotegerin, osteopontin and IL-6 serum levels were measured using an ELISA assay. Endothelial function was evaluated by flow-mediated dilation (FMD) in the brachial artery and carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness.

Results: There was no significant difference between control subjects and CAD patients according to age and sex. Compared with control subjects, CAD patients had significantly impaired FMD (p<0.001) and increased PWV (p=0.009). CAD patients also had significantly higher levels of osteoprotegerin (p<0.001), osteopontin (p<0.001) and IL-6 (p=0.03), compared with control subjects. Moreover, IL-6 levels were correlated with osteoprotegerin (r=0.17, p=0.01) and osteopontin (r=0.30, p<0.001) levels. FMD was correlated with osteoprotegerin levels independent of possible confounders [b coefficient= - 0.79, 95% CI (-1.54, -0.05), p=0.04].

Conclusion: CAD patients have increased osteoprotegerin, osteopontin and IL-6 levels. Moreover, there is a consistent association between osteoprotegerin and osteopontin serum levels, vascular function and inflammation in CAD patients. These findings suggest another possible mechanism linking osteoprotegerin and osteopontin serum levels with CAD progression through arterial wall stiffening and inflammation.

Keywords: Vascular calcification, osteoprotegerin, osteopontin, inflammation, interleukin-6, endothelial function, arterial stiffness, coronary artery disease.

Graphical Abstract

[1]
Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352(16): 1685-95.
[http://dx.doi.org/10.1056/NEJMra043430 ] [PMID: 15843671]
[2]
Shishehbor MH, Bhatt DL. Inflammation and atherosclerosis. Curr Atheroscler Rep 2004; 6(2): 131-9.
[http://dx.doi.org/10.1007/s11883-004-0102-x ] [PMID: 15023298]
[3]
Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340(2): 115-26.
[http://dx.doi.org/10.1056/NEJM199901143400207 ] [PMID: 9887164]
[4]
Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375(9709): 132-40.
[http://dx.doi.org/10.1016/S0140-6736(09)61717-7 ] [PMID: 20031199]
[5]
Danesh J, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005; 294(14): 1799-809.
[PMID: 16219884]
[6]
Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004; 351(25): 2599-610.
[http://dx.doi.org/10.1056/NEJMoa040967 ] [PMID: 15602020]
[7]
Tousoulis D, Siasos G, Maniatis K, et al. Novel biomarkers assessing the calcium deposition in coronary artery disease. Curr Med Chem 2012; 19(6): 901-20.
[http://dx.doi.org/10.2174/092986712799034833 ] [PMID: 22229416]
[8]
Tschiderer L, Klingenschmid G, Nagrani R, et al. Osteoprotegerin and cardiovascular events in high-risk populations: meta-analysis of 19 prospective studies involving 27450 participants. J Am Heart Assoc 2018; 7(16) e009012
[http://dx.doi.org/10.1161/JAHA.118.009012 ] [PMID: 30369329]
[9]
Cho HJ, Cho HJ, Kim HS. Osteopontin: a multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification. Curr Atheroscler Rep 2009; 11(3): 206-13.
[http://dx.doi.org/10.1007/s11883-009-0032-8 ] [PMID: 19361352]
[10]
Ashkar S, Weber GF, Panoutsakopoulou V, et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 2000; 287(5454): 860-4.
[http://dx.doi.org/10.1126/science.287.5454.860 ] [PMID: 10657301]
[11]
Isoda K, Nishikawa K, Kamezawa Y, et al. Osteopontin plays an important role in the development of medial thickening and neointimal formation. Circ Res 2002; 91(1): 77-82.
[http://dx.doi.org/10.1161/01.RES.0000025268.10302.0C ] [PMID: 12114325]
[12]
Agnholt J, Kelsen J, Schack L, Hvas CL, Dahlerup JF, Sørensen ES. Osteopontin, a protein with cytokine-like properties, is associated with inflammation in Crohn’s disease. Scand J Immunol 2007; 65(5): 453-60.
[http://dx.doi.org/10.1111/j.1365-3083.2007.01908.x ] [PMID: 17444956]
[13]
Komine-Aizawa S, Masuda H, Mazaki T, Shiono M, Hayakawa S, Takayama T. Plasma osteopontin predicts inflammatory bowel disease activities. Int Surg 2015; 100(1): 38-43.
[http://dx.doi.org/10.9738/INTSURG-D-13-00160.1 ] [PMID: 25594638]
[14]
Roytblat L, Rachinsky M, Fisher A, et al. Raised interleukin-6 levels in obese patients. Obes Res 2000; 8(9): 673-5.
[http://dx.doi.org/10.1038/oby.2000.86 ] [PMID: 11225716]
[15]
Pedersen M, Bruunsgaard H, Weis N, et al. Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes. Mech Ageing Dev 2003; 124(4): 495-502.
[http://dx.doi.org/10.1016/S0047-6374(03)00027-7 ] [PMID: 12714258]
[16]
Khosla S. The OPG/RANKL/RANK system. Endocrinology 2001; 142(12): 5050-5.
[http://dx.doi.org/10.1210/endo.142.12.8536 ] [PMID: 11713196]
[17]
Dienz O, Rincon M. The effects of IL-6 on CD4 T cell responses. Clin Immunol 2009; 130(1): 27-33.
[http://dx.doi.org/10.1016/j.clim.2008.08.018 ] [PMID: 18845487]
[18]
Rauramaa R, Väisänen SB, Luong LA, et al. Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis. Arterioscler Thromb Vasc Biol 2000; 20(12): 2657-62.
[http://dx.doi.org/10.1161/01.ATV.20.12.2657 ] [PMID: 11116068]
[19]
Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998; 128(2): 127-37.
[http://dx.doi.org/10.7326/0003-4819-128-2-199801150-00009 ] [PMID: 9441573]
[20]
Corretti MC, Anderson TJ, Benjamin EJ, et al. International brachial artery reactivity task force. guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force. J Am Coll Cardiol 2002; 39(2): 257-65.
[http://dx.doi.org/10.1016/S0735-1097(01)01746-6 ] [PMID: 11788217]
[21]
Rajzer MW, Wojciechowska W, Klocek M, Palka I, Brzozowska-Kiszka M, Kawecka-Jaszcz K. Comparison of aortic pulse wave velocity measured by three techniques: Complior, SphygmoCor and Arteriograph. J Hypertens 2008; 26(10): 2001-7.
[http://dx.doi.org/10.1097/HJH.0b013e32830a4a25 ] [PMID: 18806624]
[22]
Alexander RW. Inflammation and coronary artery disease. N Engl J Med 1994; 331(7): 468-9.
[http://dx.doi.org/10.1056/NEJM199408183310709 ] [PMID: 8035844]
[23]
Blankenberg S, Rupprecht HJ, Bickel C, et al. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 2001; 104(12): 1336-42.
[http://dx.doi.org/10.1161/hc3701.095949 ] [PMID: 11560847]
[24]
Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12(3): 204-12.
[http://dx.doi.org/10.1038/ni.2001 ] [PMID: 21321594]
[25]
Sun J, Sukhova GK, Wolters PJ, et al. Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med 2007; 13(6): 719-24.
[http://dx.doi.org/10.1038/nm1601 ] [PMID: 17546038]
[26]
Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med 2017; 377(12): 1119-31.
[http://dx.doi.org/10.1056/NEJMoa1707914 ] [PMID: 28845751]
[27]
Tousoulis D, Oikonomou E, Economou EK, Crea F, Kaski JC. Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur Heart J 2016; 37(22): 1723-32.
[http://dx.doi.org/10.1093/eurheartj/ehv759 ] [PMID: 26843277]
[28]
Rus HG, Vlaicu R, Niculescu F. Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 1996; 127(2): 263-71.
[http://dx.doi.org/10.1016/S0021-9150(96)05968-0 ] [PMID: 9125317]
[29]
Schieffer B, Schieffer E, Hilfiker-Kleiner D, et al. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 2000; 101(12): 1372-8.
[http://dx.doi.org/10.1161/01.CIR.101.12.1372 ] [PMID: 10736279]
[30]
Marini A, Naka KK, Vakalis K, et al. Extent of coronary artery disease in patients undergoing angiography for stable or acute coronary syndromes. Hellenic J Cardiol 2017; 58(2): 115-21.
[http://dx.doi.org/10.1016/j.hjc.2016.08.004 ] [PMID: 28495650]
[31]
Siasos G, Oikonomou E, Maniatis K, et al. Prognostic signifi-cance of arterial stiffness and osteoprotegerin in patients with stable coronary artery disease. Eur J Clin Invest 2018; 48
[http://dx.doi.org/10.1111/eci.12890] [PMID: 29330911]
[32]
Siasos G, Tousoulis D, Oikonomou E, et al. Vitamin D3, D2 and arterial wall properties in coronary artery disease. Curr Pharm Des 2014; 20(37): 5914-8.
[http://dx.doi.org/10.2174/1381612820666140619122937 ] [PMID: 24947585]
[33]
Tousoulis D, Siasos G, Maniatis K, et al. Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease. Int J Cardiol 2013; 167(5): 1924-8.
[http://dx.doi.org/10.1016/j.ijcard.2012.05.001 ] [PMID: 22640692]
[34]
Abdel-Azeez HA, Al-Zaky M. Plasma osteopontin as a predictor of coronary artery disease: association with echocardiographic characteristics of atherosclerosis. J Clin Lab Anal 2010; 24(3): 201-6.
[http://dx.doi.org/10.1002/jcla.20378 ] [PMID: 20486203]
[35]
Mohamadpour AH, Abdolrahmani L, Mirzaei H, et al. Serum osteopontin concentrations in relation to coronary artery disease. Arch Med Res 2015; 46(2): 112-7.
[http://dx.doi.org/10.1016/j.arcmed.2015.02.005 ] [PMID: 25743929]
[36]
Psarras S, Mavroidis M, Sanoudou D, et al. Regulation of adverse remodelling by osteopontin in a genetic heart failure model. Eur Heart J 2012; 33(15): 1954-63.
[http://dx.doi.org/10.1093/eurheartj/ehr119 ] [PMID: 21525025]
[37]
Jono S, Ikari Y, Shioi A, et al. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002; 106(10): 1192-4.
[http://dx.doi.org/10.1161/01.CIR.0000031524.49139.29 ] [PMID: 12208791]
[38]
Kiechl S, Schett G, Wenning G, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation 2004; 109(18): 2175-80.
[http://dx.doi.org/10.1161/01.CIR.0000127957.43874.BB ] [PMID: 15117849]
[39]
Aryan M, Kepez A, Atalar E, et al. Association of plasma osteopontin levels with coronary calcification evaluated by tomographic coronary calcium scoring. J Bone Miner Metab 2009; 27(5): 591-7.
[http://dx.doi.org/10.1007/s00774-009-0078-2 ] [PMID: 19365701]
[40]
Atalar E, Ozturk E, Ozer N, et al. Plasma soluble osteopontin concentrations are increased in patients with rheumatic mitral stenosis and associated with the severity of mitral valve calcium. Am J Cardiol 2006; 98(6): 817-20.
[http://dx.doi.org/10.1016/j.amjcard.2006.04.019 ] [PMID: 16950193]
[41]
Matsui Y, Rittling SR, Okamoto H, et al. Osteopontin deficiency attenuates atherosclerosis in female apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2003; 23(6): 1029-34.
[http://dx.doi.org/10.1161/01.ATV.0000074878.29805.D0 ] [PMID: 12730087]
[42]
Ström A, Franzén A, Wängnerud C, Knutsson AK, Heinegård D, Hultgårdh-Nilsson A. Altered vascular remodeling in osteopontin-deficient atherosclerotic mice. J Vasc Res 2004; 41(4): 314-22.
[http://dx.doi.org/10.1159/000079205 ] [PMID: 15218333]
[43]
Bruemmer D, Collins AR, Noh G, et al. Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. J Clin Invest 2003; 112(9): 1318-31.
[http://dx.doi.org/10.1172/JCI200318141 ] [PMID: 14597759]
[44]
Lund SA, Giachelli CM, Scatena M. The role of osteopontin in inflammatory processes. J Cell Commun Signal 2009; 3(3-4): 311-22.
[http://dx.doi.org/10.1007/s12079-009-0068-0 ] [PMID: 19798593]
[45]
Sennels H, Sørensen S, Ostergaard M, et al. Circulating levels of osteopontin, osteoprotegerin, total soluble receptor activator of nuclear factor-kappa B ligand, and high-sensitivity C-reactive protein in patients with active rheumatoid arthritis randomized to etanercept alone or in combination with methotrexate. Scand J Rheumatol 2008; 37(4): 241-7.
[http://dx.doi.org/10.1080/03009740801910320 ] [PMID: 18612923]
[46]
Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM. Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res 1994; 74(2): 214-24.
[http://dx.doi.org/10.1161/01.RES.74.2.214 ] [PMID: 8293561]
[47]
Panda D, Kundu GC, Lee BI, et al. Potential roles of osteopontin and alphaVbeta3 integrin in the development of coronary artery restenosis after angioplasty. Proc Natl Acad Sci USA 1997; 94(17): 9308-13.
[http://dx.doi.org/10.1073/pnas.94.17.9308 ] [PMID: 9256478]
[48]
Hirota S, Imakita M, Kohri K, et al. Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques. A possible association with calcification. Am J Pathol 1993; 143(4): 1003-8.
[PMID: 8213995]
[49]
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423(6937): 337-42.
[http://dx.doi.org/10.1038/nature01658 ] [PMID: 12748652]
[50]
Venuraju SM, Yerramasu A, Corder R, Lahiri A. Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity. J Am Coll Cardiol 2010; 55(19): 2049-61.
[http://dx.doi.org/10.1016/j.jacc.2010.03.013 ] [PMID: 20447527]
[51]
Abedin M, Omland T, Ueland T, et al. Relation of osteoprotegerin to coronary calcium and aortic plaque (from the Dallas Heart Study). Am J Cardiol 2007; 99(4): 513-8.
[http://dx.doi.org/10.1016/j.amjcard.2006.08.064 ] [PMID: 17293196]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy