Advertisement

Facilitatory effects of fetuin-A on atherosclerosis

      Highlights

      • This study is the first to demonstrate the stimulatory effects of fetuin-A on atherosclerosis.
      • Fetuin-A stimulates endothelial inflammation, macrophage foam cell formation, smooth muscle cell proliferation, and collagen production in a serum-free culture system.
      • Fetuin-A is expressed at high levels in atherosclerotic and restenotic lesions.

      Abstract

      Objective

      Fetuin-A is a circulating glycoprotein that is produced by liver and adipose tissue. Fetuin-A is known to induce insulin resistance and suppress vascular calcification. There are conflicting reports that show increased or decreased serum fetuin-A levels in patients with coronary artery disease (CAD). Since the role of fetuin-A in atherosclerosis remains still controversial, we aimed to clarify it in this study.

      Methods

      We investigated the expression of fetuin-A in atheromatous plaques in CAD patients and restenosis lesions in balloon-injured rat carotid arteries in vivo. We also assessed in vitro effects of fetuin-A on inflammatory molecules in human umbilical vein endothelial cells (HUVECs), oxidized low-density lipoprotein-induced foam cell formation in human monocyte-derived macrophages, and the migration, proliferation, and extracellular matrix expression in human aortic smooth muscle cells (HASMCs) in a serum-free culture system.

      Results

      Fetuin-A was abundantly expressed in cultured human monocytes, macrophages, fibroblasts, HASMCs, and human coronary artery SMCs, atheromatous plaques in human coronary arteries, and restenosis lesions in rat carotid arteries. In vitro experiments showed that fetuin-A stimulated interleukin-6, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and E-selectin expression in HUVECs. Fetuin-A enhanced macrophage foam cell formation associated with scavenger receptors (CD36 and SR-A) and acyl-CoA:cholesterol acyltransferase-1 down-regulation and ATP-binding cassette transporter A1 up-regulation, and increased cell proliferation and collagen-1 and -3 expression via PI3K/AKT/c-Src/NF-κB/ERK1/2 pathways in HASMCs.

      Conclusion

      Our results indicate that fetuin-A exerts the stimulatory effects on inflammatory responses in HUVECs, macrophage foam cell formation, and proliferation and collagen production in HASMCs, leading to the development of atherosclerosis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ross R.
        • Agius L.
        The process of atherogenesis−cellular and molecular interaction: from experimental animal models to humans.
        Diabetologia. 1992; 35: S34-S40
        • Allahverdian S.
        • Pannu P.S.
        • Francis G.A.
        Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation.
        Cardiovasc. Res. 2012; 95: 165-172
        • Denecke B.
        • Gräber S.
        • Schäfer C.
        • Heiss A.
        • Wöltje M.
        • Jahnen-Dechent W.
        Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A.
        Biochem. J. 2003; 376: 135-145
        • Jialal I.
        • Devaraj S.
        • Bettaieb A.
        • Haj F.
        • Adams-Huet B.
        Increased adiose tissue secretion of fetuin-A, lipopolysaccharide-binding protein and high-mobility group box protein 1 in metabolic syndrome.
        Atherosclerosis. 2015; 241: 130-137
        • Reynolds J.L.
        • Skepper J.N.
        • McNair R.
        • Kasama T.
        • Gupta K.
        • Weissberg P.L.
        • Jahnen-Dechent W.
        • Shanahan C.M.
        Multifunctional roles for serum protein fetuin-A in inhibition of human vascular smooth muscle cell calcification.
        J. Am. Soc. Nephrol. 2005; 16: 2920-2930
        • Singh M.
        • Sharma P.K.
        • Garg V.K.
        • Mondal S.C.
        • Singh A.K.
        • Kumar N.
        Role of fetuin-A in atherosclerosis associated with diabetic patients.
        J. Pharm. Pharmacol. 2012; 64: 1703-1708
        • Mori K.
        • Emoto M.
        • Inaba M.
        Fetuin-A and the cardiovascular system.
        Adv. Clin. Chem. 2012; 56: 175-195
        • Chatterjee P.
        • Seal S.
        • Mukherjee S.
        • Kundu R.
        • Mukherjee S.
        • Ray S.
        • Mukhopadhyay S.
        • Majumdar S.S.
        • Bhattacharya S.
        Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages.
        J. Biol. Chem. 2013; 288: 28324-28330
        • Hennige A.M.
        • Staiger H.
        • Wicke C.
        • Machicao F.
        • Fritsche A.
        • Häring H.U.
        • Stefan N.
        Fetuin-A induces cytokine expression and suppresses adiponectin production.
        PLoS One. 2008; 3: e1765
        • Siegel-Axel D.I.
        • Ullrich S.
        • Stefan N.
        • Rittig K.
        • Gerst F.
        • Klingler C.
        • Schmidt U.
        • Schreiner B.
        • Randrianarisoa E.
        • Schaller H.E.
        • Stock U.A.
        • Weigert C.
        • Königsrainer A.
        • Häring H.U.
        Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells.
        Diabetologia. 2014; 57: 1057-1066
        • Wang H.
        • Zhang M.
        • Bianchi M.
        • Sherry B.
        • Sama A.
        • Tracey K.J.
        Fetuin (α2-HS-glycoprotein) opsonizes cationic macrophage deactivating molecules.
        Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 14429-14434
        • Demetriou M.
        • Binkert C.
        • Sukhu B.
        • Tenenbaum H.C.
        • Dennis J.W.
        Fetuin/α2-HS glycoprotein is a transforming growth factor-β type II receptor mimic and cytokine antagonist.
        J. Biol. Chem. 1996; 271: 12755-12761
        • Daveau M.
        • Davrinche C.
        • Julen N.
        • Hiron M.
        • Arnaud P.
        • Lebreton J.P.
        The synthesis of human α2-HS glycoprotein is down-regulated by cytokines in hepatoma HepG2 cells.
        FEBS Lett. 1988; 241: 191-194
        • Ray S.
        • Lukyanov P.
        • Ochieng J.
        Members of the cystatin superfamily interact with MMP-9 and protect it from autolytic degradation without affecting its gelatinolytic activities.
        Biochim. Biophys. Acta. 2003; 1652: 91-102
        • Sun Z.L.
        • Xie Q.Y.
        • Guo G.L.
        • Ma K.
        • Huang Y.Y.
        Serum fetuin-A levels in patients with cardiovascular disease: a meta-analysis.
        Biomed. Res. Int. 2014; 2014: 691540
        • Szeberin Z.
        • Fehérvári M.
        • Krepuska M.
        • Apor A.
        • Rimely E.
        • Sarkadi H.
        • Széplaki G.
        • Prohászka Z.
        • Kalabay L.
        • Acsády G.
        Serum fetuin-A levels inversely correlate with the severity of arterial calcification in patients with chronic lower extremity atherosclerosis without renal disease.
        Int. Angiol. 2011; 30: 474-480
        • Mori K.
        • Ikari Y.
        • Jono S.
        • Emoto M.
        • Shioi A.
        • Koyama H.
        • Shoji T.
        • Ishimura E.
        • Inaba M.
        • Hara K.
        • Nishizawa Y.
        Fetuin-A is associated with calcified coronary artery disease.
        Coron. Artery Dis. 2010; 21: 281-285
        • Ix J.H.
        • Katz R.
        • de Boer I.H.
        • Kestenbaum B.R.
        • Peralta C.A.
        • Jenny N.S.
        • Budoff M.
        • Allison M.A.
        • Criqui M.H.
        • Siscovick D.
        • Shlipak M.G.
        Fetuin-A is inversely associated with coronary artery calcification in community-living persons: the multi-ethnic study of atherosclerosis.
        Clin. Chem. 2012; 58: 887-895
        • Weikert C.
        • Stefan N.
        • Schulze M.B.
        • Pischon T.
        • Berger K.
        • Joost H.G.
        • Häring H.U.
        • Boeing H.
        • Fritsche A.
        Plasma fetuin-A levels and the risk of myocardial infarction and ischemic stroke.
        Circulation. 2008; 118: 2555-2562
        • Bilgir O.
        • Kebapcilar L.
        • Bilgir F.
        • Bozkaya G.
        • Yildiz Y.
        • Pinar P.
        • Tastan A.
        Decreased serum fetuin-A levels are associated with coronary artery diseases.
        Intern. Med. 2010; 49: 1281-1285
        • Vörös K.
        • Gráf Jr., L.
        • Prohászka Z.
        • Gráf L.
        • Szenthe P.
        • Kaszás E.
        • Böröcz Z.
        • Cseh K.
        • Kalabay L.
        Serum fetuin-A in metabolic and inflammatory pathways in patients with myocardial infarction.
        Eur. J. Clin. Investig. 2011; 41: 703-709
        • Zhao Z.W.
        • Lin C.G.
        • Wu L.Z.
        • Luo Y.K.
        • Fan L.
        • Dong X.F.
        • Zheng H.
        Serum fetuin-A levels are associated with the presence and severity of coronary artery disease in patients with type 2 diabetes.
        Biomarkers. 2013; 18: 160-164
        • Lim P.
        • Montereau S.
        • Simon T.
        • Gallet R.
        • Probst V.
        • Ferrieres J.
        • Gueret P.
        • Danchin N.
        Usefulness of fetuin-A and C-reactive protein concentrations for prediction of outcome in acute coronary syndromes (from the French registry of acute ST-Elevation Non-ST-Elevation myocardial infarction [FAST-MI]).
        Am. J. Cardiol. 2013; 111: 31-37
        • Sun Q.
        • Jiménez M.C.
        • Townsend M.K.
        • Townsend M.K.
        • Rimm E.B.
        • Manson J.E.
        • Albert C.M.
        • Rexrode K.M.
        Plasma levels of fetuin-A and risk of coronary heart disease in US women: the Nurses' health Study.
        J. Am. Heart Assoc. 2014; 3: e000939
        • Coker-Gurkan A.
        • Coskun D.
        • Arisan E.D.
        • Obakan P.
        • Soylu O.
        • Unsal N.P.
        Fetuin-A 742 (C/T) and 766 (C/G) polymorphic sites are associated with increased risk of myocardial infarction in older patients (≥40 years of age).
        Mol. Med. Rep. 2015; 12: 1356-1362
        • Watanabe T.
        • Nishio K.
        • Kanome T.
        • Matsuyama T.
        • Koba S.
        • Sakai T.
        • Sato K.
        • Hongo S.
        • Nose K.
        • Ota H.
        • Kobayashi Y.
        • Katagiri T.
        • Shichiri M.
        • Miyazaki A.
        Impact of salusin-α and -β on human macrophage foam cell formation and coronary atherosclerosis.
        Circulation. 2008; 117: 638-648
        • Xu G.
        • Watanabe T.
        • Iso Y.
        • Koba S.
        • Sakai T.
        • Nagashima M.
        • Arita S.
        • Hongo S.
        • Ota H.
        • Kobayashi Y.
        • Miyazaki A.
        • Hirano T.
        Preventive effects of heregulin-β1 on macrophage foam cell formation and atherosclerosis.
        Circ. Res. 2009; 105: 500-510
        • Konii H.
        • Sato K.
        • Kikuchi S.
        • Okiyama H.
        • Watanabe R.
        • Hasegawa A.
        • Yamamoto K.
        • Itoh F.
        • Hirano T.
        • Watanabe T.
        Stimulatory effects of cardiotrophin 1 on atherosclerosis.
        Hypertension. 2013; 62: 942-950
        • Hasegawa A.
        • Sato K.
        • Shirai R.
        • Watanabe R.
        • Yamamoto K.
        • Watanabe K.
        • Nohtomi K.
        • Hirano T.
        • Watanabe T.
        Vasoprotective effects of urocortin 1 against atherosclerosis in vitro and in vivo.
        PLoS One. 2014; 9: e110866
        • Watanabe T.
        • Suguro T.
        • Kanome T.
        • Sakamoto Y.
        • Kodate S.
        • Hagiwara T.
        • Hongo S.
        • Hirano T.
        • Adachi M.
        • Miyazaki A.
        Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages.
        Hypertension. 2005; 46: 738-744
        • Watanabe K.
        • Watanabe R.
        • Konii H.
        • Shirai R.
        • Sato K.
        • Matsuyama T.
        • Ishibashi-Ueda H.
        • Koba S.
        • Kobayashi Y.
        • Hirano T.
        • Watanabe T.
        Counteractive effects of omentin-1 against atherogenesis.
        Cardiovasc Res. 2015; (in press)
        • Mukhopadhyay S.
        • Mondal S.A.
        • Kumar M.
        • Dutta D.
        Proinflammatory and antiinflammatory attributes of fetuin-A: a novel hepatokine modulating cardiovascular and glycemic outcomes in metabolic syndrome.
        Endocr. Pract. 2014; 20: 1345-1351
        • Wang H.
        • Li W.
        • Zhu S.
        • Li J.
        • D'Amore J.
        • Ward M.F.
        • Yang H.
        • Wu R.
        • Jahnen-Dechent W.
        • Tracey K.J.
        • Wang P.
        • Sama A.E.
        Peripheral administration of fetuin-A attenuates early cerebral ischemic injury in rats.
        J. Cereb. Blood Flow. Metab. 2010; 30: 493-504
        • Merx M.W.
        • Schäfer C.
        • Westenfeld R.
        • Brandenburg V.
        • Hidajat S.
        • Weber C.
        • Ketteler M.
        • Jahnen-Dechent W.
        Myocardial stiffness, cardiac remodeling, and diastolic dysfunction in calcification-prone fetuin-A-deficient mice.
        J. Am. Soc. Nephrol. 2005; 16: 3357-3364
        • Westenfeld R.
        • Schäfer C.
        • Krüger T.
        • Haarmann C.
        • Schurgers L.J.
        • Reutelingsperger C.
        • Ivanovski O.
        • Drueke T.
        • Massy Z.A.
        • Ketteler M.
        • Floege J.
        • Jahnen-Dechent W.
        Fetuin-A protects against atherosclerotic calcification in CKD.
        J. Am. Soc. Nephrol. 2009; 20: 1264-1274
        • Fiore C.E.
        • Celotta G.
        • Politi G.G.
        • Di Pino L.
        • Castelli Z.
        • Mangiafico R.A.
        • Signorelli S.S.
        • Pennisi P.
        Association of high alpha2-Heremans-Schmid glycoprotein/fetuin concentration in serum and intima-media thickness in patients with atherosclerotic vascular disease and low bone mass.
        Atherosclerosis. 2007; 195: 110-115
        • Rittig K.
        • Thamer C.
        • Haupt A.
        • Machann J.
        • Peter A.
        • Balletshofer B.
        • Fritsche A.
        • Haring H.U.
        • Stefan N.
        High plasma fetuin-A is associated with increased carotid intima-media thickness in a middle-aged population.
        Atherosclerosis. 2009; 207: 341-342
        • Tuttolomondo A.
        • Di Raimondo D.
        • Di Sciacca R.
        • Casuccio A.
        • Bivona G.
        • Bellia C.
        • Barreca L.
        • Serio A.
        • D'Aguanno G.
        • Ciaccio M.
        • Licata G.
        • Pinto A.
        Fetuin-A and CD40 L plasma levels in acute ischemic stroke: differences in relation to TOAST subtype and correlation with clinical and laboratory variables.
        Atherosclerosis. 2010; 208: 290-296
        • Wang A.Y.
        • Woo J.
        • Lam C.W.
        • Wang M.
        • Chan I.H.
        • Gao P.
        • Lui S.
        • Li P.K.
        • Sanderson J.E.
        Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients.
        Nephrol. Dial. Transpl. 2005; 20: 1676-1685
        • Dogru T.
        • Genc H.
        • Tapan S.
        • Aslan F.
        • Ercin C.N.
        • Ors F.
        • Kara M.
        • Sertoglu E.
        • Karslioglu Y.
        • Bagci S.
        • Kurt I.
        • Sonmez A.
        Plasma fetuin-A is associated with endothelial dysfunction and subclinical atherosclerosis in subjects with nonalcoholic fatty liver disease.
        Clin. Endocrinol. Oxf. 2013; 78: 712-717
        • Aydin F.N.
        • Agilli M.
        • Cayci T.
        • Kurt Y.G.
        The effect of serum fetuin-A on atherosclerosis in hemodialysis patients.
        Saudi. J. Kidney Dis. Transpl. 2015; 26: 370-371
        • Koluman B.U.
        • Mutluay R.
        • Derici U.B.
        • Arinsoy T.
        • Senlik Z.
        • Bahar B.
        • Sancak B.
        • Oktan S.O.
        • Sindel S.
        Association between osteoprotegerin, fetuin-A, carotid intima media thickness, and urinary albumin excretion in type 2 diabetes.
        Clin. Nephrol. 2013; 80: 9-16
        • Ozturk K.
        • Uygun A.
        • Guler A.K.
        • Demirci H.
        • Ozdemir C.
        • Cakir M.
        • Sakin Y.S.
        • Turker T.
        • Sari S.
        • Demirbas S.
        • Karslıoğlu Y.
        • Saglam M.
        Nonalcoholic fatty liver disease is an independent risk factor for atherosclerosis in young adult men.
        Atherosclerosis. 2015; 240: 380-386
        • Beddhu S.
        • Kaysen G.A.
        • Yan G.
        • Sarnak M.
        • Agodoa L.
        • Ornt D.
        • Cheung A.K.
        • HEMO Study Group
        Association of serum albumin and atherosclerosis in chronic hemodialysis patients.
        Am. J. Kidney Dis. 2002; 40: 721-727
        • Joki N.
        • Hase H.
        • Tanaka Y.
        • Takahashi Y.
        • Saijyo T.
        • Ishikawa H.
        • Inishi Y.
        • Imamura Y.
        • Hara H.
        • Tsunoda T.
        • Nakamura M.
        Relationship between serum albumin level before initiating haemodialysis and angiographic severity of coronary atherosclerosis in end-stage renal disease patients.
        Nephrol. Dial. Transpl. 2006; 21: 1633-1639
        • Wu C.Y.
        • Martel J.
        • Young D.
        • Young J.D.
        Fetuin-A/albumin-mineral complexes resembling serum calcium granules and putative nanobacteria: demonstration of a dual inhibition-seeding concept.
        PLoS One. 2009; 4: e8058
        • Smith E.R.
        • Hanssen E.
        • McMahon L.P.
        • Holt S.G.
        Fetuin-A-containing calciprotein particles reduce mineral stress in the macrophage.
        PLoS One. 2013; 8: e60904
        • Dautova Y.
        • Kozlova D.
        • Skepper J.N.
        • Epple M.
        • Bootman M.D.
        • Proudfoot D.
        Fetuin-A and albumin alter cytotoxic effects of calcium phosphate nanoparticles on human vascular smooth muscle cells.
        PLoS One. 2014; 9: e97565
        • Leosco D.
        • Fineschi M.
        • Pierli C.
        • Fiaschi A.
        • Ferrara N.
        • Bianco S.
        • Longobardi G.
        • Pisani E.
        • Bravi A.
        • Rengo F.
        Intracoronary serotonin release after high-pressure coronary stenting.
        Am. J. Cardiol. 1999; 84: 1317-1322
        • Cartellieri S.
        • Hamer O.
        • Helmholz H.
        • Niemeyer B.
        One-step affinity purification of fetuin from fetal bovine serum.
        Biotechnol. Appl. Biochem. 2002; 35: 83-89

      Linked Article

      • Corrigendum to “Facilitatory effects of fetuin-A on atherosclerosis” [Atherosclerosis 246 (2016) 344–351]
        AtherosclerosisVol. 253
        • Preview
          The authors regret a mistake in the Abstract of the original version of the article. In the Abstract, the sentence: “Fetuin-A enhanced macrophage foam cell formation associated with scavenger receptors (CD36 and SR-A) and acyl-CoA:cholesterol acyltransferase-1 down-regulation and ATP-binding cassette transporter A1 up-regulation, and increased cell proliferation and collagen-1 and -3 expression via PI3K/AKT/c-Src/NF-κB/ERK1/2 pathways in HASMCs” is corrected as follows: “Fetuin-A enhanced macrophage foam cell formation associated with scavenger receptors (CD36 and SR-A) and acyl-CoA:cholesterol acyltransferase-1 up-regulation and ATP-binding cassette transporter A1 down-regulation, and increased cell proliferation and collagen-1 and -3 expression via PI3K/AKT/c-Src/NF-κB/ERK1/2 pathways in HASMCs.”
        • Full-Text
        • PDF