Pentraxin 3 and complement cascade activation in the failure of arteriovenous fistula



      Pentraxin-3 (PTX3) has been suggested to play a role in the development of vascular pathology. Stenosis of arteriovenous fistula (AVF) leading to its failure is the major cause of morbidity in hemodialysis patients. To date, little is known on the pathogenesis of AVF stenosis. The aim of the present study was to investigate the potential role of PTX3 in this setting.

      Methods and results

      A sample of venous wall was collected at the time of AVF formation in 44 patients with end stage renal disease. Ten patients developed AVF stenosis and from these patients a second portion of the venous wall was obtained during surgical revision of the AVF. Confocal laser scanning microscopy demonstrated that PTX3 immunostaining, hardly detectable in native AVF, was significantly increased in failed AVF, showing a specific co-localization with endothelial cell markers. Circulating mononuclear cells isolated at the time of AVF revision presented a significantly higher PTX3 mRNA expression than those collected during AVF creation. Interestingly, a significant deposition of C5b-9 on endothelial cells, co-localizing with PTX3, was observed in stenotic AVF.


      The present study demonstrates for the first time a close association between PTX3 deposition and complement activation at the endothelial cell level in failed AVF and suggests a role for PTX3 in modulating innate immunity in the pathogenesis of AVF stenosis.


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


        • Binder C.J.
        • Chang M.K.
        • Shaw P.X.
        • et al.
        Innate and acquired immunity in atherogenesis.
        Nat Med. 2002; 8: 1218-1226
        • Glass C.K.
        • Witztum J.L.
        Atherosclerosis. The road ahead.
        Cell. 2001; 104: 503-516
        • Hansson G.K.
        Immune mechanisms in atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1876-1890
        • Garlanda C.
        • Bottazzi B.
        • Bastone A.
        • Mantovani A.
        Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility.
        Annu Rev Immunol. 2005; 23: 337-366
        • Peri G.
        • Introna M.
        • Corradi D.
        • et al.
        PTX3, a prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans.
        Circulation. 2000; 102: 636-641
        • Mantovani A.
        • Garlanda C.
        • Bottazzi B.
        • et al.
        The long pentraxin PTX3 in vascular pathology.
        Vascul Pharmacol. 2006; 45: 326-330
        • Rolph M.S.
        • Zimmer S.
        • Bottazzi B.
        • Garlanda C.
        • Mantovani A.
        • Hansson G.K.
        Production of the long pentraxin PTX3 in advanced atherosclerotic plaques.
        Arterioscler Thromb Vasc Biol. 2002; 22: e10-e14
        • van Rossum A.P.
        • Pas H.H.
        • Fazzini F.
        • et al.
        Abundance of the long pentraxin PTX3 at sites of leukocytoclastic lesions in patients with small-vessel vasculitis.
        Arthritis Rheum. 2006; 54: 986-991
        • Baruah P.
        • Dumitriu I.E.
        • Peri G.
        • et al.
        The tissue pentraxin PTX3 limits C1q-mediated complement activation and phagocytosis of apoptotic cells by dendritic cells.
        J Leukoc Biol. 2006; 80: 87-95
        • Nauta A.J.
        • Bottazzi B.
        • Mantovani A.
        • et al.
        Biochemical and functional characterization of the interaction between pentraxin 3 and C1q.
        Eur J Immunol. 2003; 33: 465-473
        • Oksjoki R.
        • Kovanen P.T.
        • Meri S.
        • Pentikainen M.O.
        Function and regulation of the complement system in cardiovascular diseases.
        Front Biosci. 2007; 12: 4696-4708
        • Fosbrink M.
        • Niculescu F.
        • Rus V.
        • Shin M.L.
        • Rus H.
        C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1.
        J Biol Chem. 2006; 281: 19009-19018
        • Feldman H.I.
        • Kobrin S.
        • Wasserstein A.
        Hemodialysis vascular access morbidity.
        J Am Soc Nephrol. 1996; 7: 523-535
        • Roy-Chaudhury P.
        • Sukhatme V.P.
        • Cheung A.K.
        Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint.
        J Am Soc Nephrol. 2006; 17: 1112-1127
        • Roy-Chaudhury P.
        • Arend L.
        • Zhang J.
        • et al.
        Neointimal hyperplasia in early arteriovenous fistula failure.
        Am J Kidney Dis. 2007; 50: 782-790
        • Wang Y.
        • Krishnamoorthy M.
        • Banerjee R.
        • et al.
        Venous stenosis in a pig arteriovenous fistula model—anatomy, mechanisms and cellular phenotypes.
        Nephrol Dial Transplant. 2008; 23: 525-533
        • Castellano G.
        • Woltman A.M.
        • Nauta A.J.
        • et al.
        Maturation of dendritic cells abrogates C1q production in vivo and in vitro.
        Blood. 2004; 103: 3813-3820
        • Marrone D.
        • Pertosa G.
        • Simone S.
        • et al.
        Local activation of interleukin 6 signaling is associated with arteriovenous fistula stenosis in hemodialysis patients.
        Am J Kidney Dis. 2007; 49: 664-673
        • Hansson G.K.
        • Libby P.
        The immune response in atherosclerosis: a double-edged sword.
        Nat Rev Immunol. 2006; 6: 508-519
        • Ross R.
        Atherosclerosis—an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Presta M.
        • Camozzi M.
        • Salvatori G.
        • Rusnati M.
        Role of the soluble pattern recognition receptor PTX3 in vascular biology.
        J Cell Mol Med. 2007; 11: 723-738
        • Mantovani A.
        • Garlanda C.
        • Doni A.
        • Bottazzi B.
        Pentraxins in innate immunity: from C-reactive protein to the long Pentraxin PTX3.
        J Clin Immunol. 2008; 28: 1-13
        • Boehme M.
        • Kaehne F.
        • Kuehne A.
        • et al.
        Pentraxin 3 is elevated in haemodialysis patients and is associated with cardiovascular disease.
        Nephrol Dial Transplant. 2007; 22: 2224-2229
        • Kotooka N.
        • Inoue T.
        • Fujimatsu D.
        • et al.
        Pentraxin3 is a novel marker for stent-induced inflammation and neointimal thickening.
        Atherosclerosis. 2007; 197: 368-374
        • Napoleone E.
        • di Santo A.
        • Peri G.
        • et al.
        The long pentraxin PTX3 up-regulates tissue factor in activated monocytes: another link between inflammation and clotting activation.
        J Leukoc Biol. 2004; 76: 203-209
        • Schepers A.
        • de Vries M.R.
        • van Leuven C.J.
        • et al.
        Inhibition of complement component C3 reduces vein graft atherosclerosis in apolipoprotein E3-Leiden transgenic mice.
        Circulation. 2006; 114: 2831-2838
        • Halperin J.A.
        • Taratuska A.
        • Nicholson-Weller A.
        Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells.
        J Clin Invest. 1993; 91: 1974-1978
        • Benzaquen L.R.
        • Nicholson-Weller A.
        • Halperin J.A.
        Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells.
        J Exp Med. 1994; 179: 985-992
        • Niculescu F.
        • Badea T.
        • Rus H.
        Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase.
        Atherosclerosis. 1999; 142: 47-56
        • Torzewski J.
        • Torzewski M.
        • Bowyer D.E.
        • et al.
        C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1386-1392
        • Viedt C.
        • Hansch G.M.
        • Brandes R.P.
        • Kubler W.
        • Kreuzer J.
        The terminal complement complex C5b-9 stimulates interleukin-6 production in human smooth muscle cells through activation of transcription factors NF-kappa B and AP-1.
        FASEB J. 2000; 14: 2370-2372