Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE null mice



      There is an emerging widespread interest in the role of damage-associated molecular pattern molecules (DAMP) S100A8, S100A9 and S100A12 in cardiovascular and other diseases. In this study we tested the efficacy of ABR-215757, a S100 protein binding immuno-modulatory compound to stabilize atherosclerosis in transgenic ApoE null mice that express the human pro-inflammatory S100A12 protein within the smooth muscle cell (SM22α-S100A12).


      Twelve-week old S100A12 transgenic/ApoE−/− and WT/ApoE−/− mice were treated with ABR-21575 for 5 weeks and were analyzed 4 month later.


      Surface plasmon resonance analysis demonstrated that S100A12 interacts with ABR-215757 in a zinc dependent manner in vitro. In vivo, ABR-215757 administration reduced features of advanced plaque morphology resulting in smaller necrotic cores, diminished intimal and medial vascular calcification, and reduced amount of infiltrating inflammatory cells. ABR-215757 normalized aortic expression of RAGE protein and normalized experimentally-induced delayed hypersensitivity. The effect of ABR-215757 was more prominent in ApoE−/− mice expressing S100A12 than in ApoE−/− animals lacking expression of human S100A12 protein.


      Our data suggest that S100A12 is important for progression of atherosclerosis and can be targeted by the small molecule ABR-215757. The specific binding of quinoline-3-carboxamides to S100A12 attenuates S100A12-mediated features of accelerated murine atherosclerosis.


      • SMC-targeted expression of S100A12 accelerates atherosclerosis in apolipoprotein E deficient mice.
      • Quinoline-3-carboxamide (ABR-215757) binds to rS100A12 with slightly different kinetics than S100A9.
      • Treatment with Quinoline-3-carboxamide attenuates atherosclerosis in S100A12 transgenic and WT ApoE mice.


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        • Yan S.F.
        • Ramasamy R.
        • Schmidt A.M.
        The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature.
        Circ Res. 2010; 106: 842-853
        • Averill M.M.
        • Kerkhoff C.
        • Bornfeldt K.E.
        S100A8 and S100A9 in cardiovascular biology and disease.
        Arterioscler Thromb Vasc Biol. 2012; 32: 223-229
        • Hofmann M.A.
        • Drury S.
        • Fu C.
        • et al.
        RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.
        Cell. 1999; 97: 889-901
        • Vogl T.
        • Tenbrock K.
        • Ludwig S.
        • et al.
        Mrp8 and Mrp14 are endogenous activators of toll-like receptor 4, promoting lethal, endotoxin-induced shock.
        Nat Med. 2007; 13: 1042-1049
        • Rosenberg S.
        • Elashoff M.R.
        • Beineke P.
        • et al.
        Multicenter validation of the diagnostic accuracy of a blood-based gene expression test for assessing obstructive coronary artery disease in nondiabetic patients.
        Ann Intern Med. 2010; 153: 425-434
        • Wingrove J.A.
        • Daniels S.E.
        • Sehnert A.J.
        • et al.
        Correlation of peripheral-blood gene expression with the extent of coronary artery stenosis.
        Circ Cardiovasc Genet. 2008; 1: 31-38
        • Morrow D.A.
        • Wang Y.
        • Croce K.
        • et al.
        Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the pravastatin or atorvastatin evaluation and infection therapy: thrombolysis in myocardial infarction (PROVE IT-TIMI 22) trial.
        Am Heart J. 2008; 155: 49-55
        • Altwegg L.A.
        • Neidhart M.
        • Hersberger M.
        • et al.
        Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes.
        Eur Heart J. 2007; 28: 941-948
        • Burke A.P.
        • Kolodgie F.D.
        • Zieske A.
        • et al.
        Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1266-1271
        • Abbas A.
        • Aukrust P.
        • Dahl T.B.
        • et al.
        High levels of S100A12 are associated with recent plaque symptomatology in patients with carotid atherosclerosis.
        Stroke. 2012; 43: 1347-1353
        • Das D.
        • Gawdzik J.
        • Dellefave-Castillo L.
        • et al.
        S100A12 expression in thoracic aortic aneurysm is associated with increased risk of dissection and perioperative complications.
        J Am Coll Cardiol. 2012; 60: 775-785
        • Hofmann Bowman M.A.
        • Gawdzik J.
        • Bukhari U.
        • et al.
        S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program.
        Arterioscler Thromb Vasc Biol. 2011; 31: 337-344
        • Bjork P.
        • Bjork A.
        • Vogl T.
        • et al.
        Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides.
        PLoS Biol. 2009; 7: e97
        • Bengtsson A.A.
        • Sturfelt G.
        • Lood C.
        • et al.
        Pharmacokinetics, tolerability, and preliminary efficacy of ABR-215757, a new quinoline-3-carboxamide derivative, in murine and human SLE.
        Arthritis Rheum. 2012; 64: 1579-1588
        • Carlsten H.
        • Jonsson C.
        • Bokarewa M.
        • Svensson L.
        • Tarkowski A.
        The impact of a new immunomodulator oxo-quinoline-3-carboxamide on the progression of experimental lupus.
        Int Immunopharmacol. 2004; 4: 1515-1523
        • Comi G.
        • Jeffery D.
        • Kappos L.
        • et al.
        Placebo-controlled trial of oral laquinimod for multiple sclerosis.
        N Engl J Med. 2012; 366: 1000-1009
        • Foell D.
        • Roth J.
        Proinflammatory S100 proteins in arthritis and autoimmune disease.
        Arthritis Rheum. 2004; 50: 3762-3771
        • Hofmann Bowman M.
        • Wilk J.
        • Heydemann A.
        • et al.
        S100A12 mediates aortic wall remodeling and aortic aneurysm.
        Circ Res. 2010; 106: 145-154
        • Fuellen G.
        • Nacken W.
        • Sorg C.
        • Kerkhoff C.
        Computational searches for missing orthologs: the case of S100A12 in mice.
        OMICS. 2004; 8: 334-340
        • Yang Z.
        • Tao T.
        • Raftery M.J.
        • Youssef P.
        • Di Girolamo N.
        • Geczy C.L.
        Proinflammatory properties of the human S100 protein S100A12.
        J Leukoc Biol. 2001; 69: 986-994
        • Akirav E.M.
        • Preston-Hurlburt P.
        • Garyu J.
        • et al.
        RAGE expression in human t cells: a link between environmental factors and adaptive immune responses.
        PLoS One. 2012; 7: e34698
        • 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: 183-194
        • Sampson B.
        • Fagerhol M.K.
        • Sunderkotter C.
        • et al.
        Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism.
        Lancet. 2002; 360: 1742-1745
        • Croce K.
        • Gao H.
        • Wang Y.
        • et al.
        Myeloid-related protein-8/14 is critical for the biological response to vascular injury.
        Circulation. 2009; 120: 427-436
      1. Maiseyeu A, Badgeley MA, Kampfrath T, et al. In vivo targeting of inflammation-associated myeloid-related protein 8/14 via gadolinium immunonanoparticles. Arterioscler Thromb Vasc Biol;32:962–70.

        • Alexander M.R.
        • Moehle C.W.
        • Johnson J.L.
        • et al.
        Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice.
        J Clin Invest. 2012; 122: 70-79
        • Lunniss C.J.
        • Cooper A.W.
        • Eldred C.D.
        • et al.
        Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration.
        Bioorg Med Chem Lett. 2009; 19: 1380-1385
        • Tomassoli I.
        • Ismaili L.
        • Pudlo M.
        • et al.
        Synthesis, biological assessment and molecular modeling of new dihydroquinoline-3-carboxamides and dihydroquinoline-3-carbohydrazide derivatives as cholinesterase inhibitors, and Ca channel antagonists.
        Eur J Med Chem. 2011; 46: 1-10
        • Haga H.J.
        • Brun J.G.
        • Berntzen H.B.
        • Cervera R.
        • Khamashta M.
        • Hughes G.R.
        Calprotectin in patients with systemic lupus erythematosus: relation to clinical and laboratory parameters of disease activity.
        Lupus. 1993; 2: 47-50
        • Soyfoo M.S.
        • Roth J.
        • Vogl T.
        • Pochet R.
        • Decaux G.
        Phagocyte-specific S100A8/A9 protein levels during disease exacerbations and infections in systemic lupus erythematosus.
        J Rheumatol. 2009; 36: 2190-2194
      2. Lood C, Stenstrom M, Tyden H, et al. Protein synthesis of the pro-inflammatory S100A8/A9 complex in plasmacytoid dendritic cells and cell surface S100A8/A9 on leukocyte subpopulations in systemic lupus erythematosus. Arthritis Res Ther;13:R60.

        • Cheng P.
        • Corzo C.A.
        • Luetteke N.
        • et al.
        Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein.
        J Exp Med. 2008; 205: 2235-2249