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

      Abstract

      Objective

      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).

      Methods

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

      Results

      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.

      Conclusion

      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.

      Highlights

      • 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.

      Keywords

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