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  • 1
    Online Resource
    Online Resource
    Abstract 224: TRAF-STOP-RHDL-Nanoparticles Reduce Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 37, No. suppl_1 ( 2017-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
    Abstract: Background: Inhibition of the costimulatory CD40-CD40L receptor/ligand dyad drastically reduces atherosclerosis. However, its long-term blockage can result in immune suppression. We recently identified small molecule inhibitors that block the interaction between CD40 and TNF Receptor Associated Factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. We investigated the potential of the TRAF-STOPs to treat atherosclerosis. Results: Treatment of ApoE-/- mice with either TRAF-STOP 6877002 or 6860766 reduced both initial and established atherosclerosis and induced a stable plaque phenotype with increased collagen and VSMC content, decreased lipid core, and a decrease in macrophage number. There were no signs of immune suppression or toxicity. In vitro experiments showed that the TRAF-STOPs reduced inflammation in macrophages, but not in T- or B cells, endothelial cells or vascular smooth muscle cells. Intravital microscopy demonstrated that the TRAF-STOPs reduced monocyte recruitment to the plaque. The CD36-mediated uptake of ox-LDL by macrophages and foam cell formation was also inhibited by TRAF-STOPs. Transcriptomics analysis and Ingenuity pathway analysis of TRAF-STOP-treated bone marrow-derived macrophages revealed that the top ranking canonical pathways for both TRAF-STOPs involved pro-inflammatory immune responses and cholesterol biosynthesis. 6877002 also affected cell cycle regulation. Surface plasmon resonance experiments and mutation studies demonstrated that 6877002 and 6860766 had a different interaction site within the TRAF6 C-domain, which explained the additional effect of 6877002. To target TRAF-STOPs specifically to macrophages, 6877002 was incorporated into rHDL nanoparticles. Flowcytometry and fluorescent microscopy demonstrated accumulation of rHDL-6877002 in plaque macrophages after a single dosis. Six weeks of rHDL-6877002 treatment reduced atherosclerosis in ApoE-/- mice. Conclusions: TRAF-STOP 6877002 and 6860766 can overcome the current limitations of long-term CD40 and CD40L inhibition and nanoparticle-mediated delivery TRAF-STOP to plaque macrophages may become a future therapy for atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.224
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1494427-3
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  • 2
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    Online Resource
    Abstract 378: Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E-deficient mice
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 38, No. Suppl_1 ( 2018-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. Suppl_1 ( 2018-05)
    Abstract: Atherothrombosis is the cause of death of over 14 million people per year worldwide and murine models to replicate this process in vivo are mostly lacking. Previously we demonstrated that silencing of anticoagulant protein C using RNA interference ( siProc ) induces spontaneous atherothrombosis in the aortic root of apolipoprotein E-deficient ( Apoe -/- ) mice, albeit at a low incidence rate. Here we aim to determine if plaque susceptibility for rupture can be linked to plaque characteristics and/or blood composition, and moreover, we attempt to boost incidence through a transient increase in blood pressure as well as to localize atherothrombosis to an additional predefined vascular site by means of a semi-constrictive collar around the carotid artery. In the current study, si Proc -driven spontaneous atherothrombosis in the aortic root of Apoe-/- mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe -/- mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, and serum amyloid A were not different amongst si Proc -treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe -/- mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.38.suppl_1.378
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1494427-3
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  • 3
    Online Resource
    Online Resource
    Abstract 592: Constitutive CD40-Signaling in Dendritic Cells Limits Atherosclerosis by Provoking Inflammatory Bowel Disease and Ensuing Cholesterol Malabsorption
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 37, No. suppl_1 ( 2017-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
    Abstract: The co-stimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types including mature dendritic cells (DCs) and required for optimal T cell activation and expansion. It remains undetermined if and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here we examined the effects of constitutively active CD40 in DCs on atherosclerosis, using low-density lipoprotein-deficient (Ldlr -/- ) bone-marrow chimeras that express an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the CD11c promoter ( DC-CD40ca ). As expected, DC-CD40ca/Ldlr -/- chimeras showed increased antigen presenting capacity on DCs and increased T cell numbers. However, they developed extensive neutrophilia compared to wt / ldlr -/- chimeras. Despite overt T cell expansion and neutrophilia we observed a reduction in cDC frequency and a dramatic reduction in atherosclerosis ( CD40wt/ldlr -/- 22076±3763 μm 2 vs. DC-CD40ca/ldlr -/- 2511±1256 μm 2 ). Further analyses revealed that cholesterol and triglyceride levels decreased by 37% and 60%, respectively, in DC-CD40ca/Ldlr -/- chimeras. Moreover, DC-CD40ca/Ldlr -/- chimeras developed inflammatory bowel disease characterized by massive transmural influx of leukocytes and lymphocytes, resulting in villous degeneration and lipid malabsorption. Constitutive activation of CD40 in DCs results in inflammation of the gastrointestinal tract, thereby impairing lipid uptake, which consequently results in attenuated atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.592
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1494427-3
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  • 4
    Online Resource
    Online Resource
    Abstract 376: Traf-stop-hdl-nanoparticles Reduce Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Inhibition of the co-stimulatory CD40-CD40L receptor/ligand dyad drastically reduces atherosclerosis. However, its long-term blockage results in immune suppression. Inhibition of the CD40-CD40L dyad further downstream in the signaling pathway is therefore required. The interaction between CD40 and its signaling intermediate TNF receptor associated factor 6 (TRAF6) plays a pivotal role in atherosclerosis. To identify drug like molecules that inhibit the CD40-TRAF6 interaction, an in silico structure-based virtual ligand screening approach was used. Several small molecule inhibitors (SMI) blocking CD40-TRAF6 interactions were identified. Surface plasmon resonance experiments confirmed direct binding of the compounds to the TRAF6 C-domain. Two of these SMIs, the TRAF-STOPs, reduced atherosclerosis by 〉 40% in Apoe-/- mice, when they were treated from 12-18 wks of age, by hampering monocyte and neutrophil recruitment. In accordance, expression of chemokines and cytokines was remarkably reduced in compound treated macrophages. Interestingly, when the TRAF-STOPs were administered to mice with existing atherosclerosis (from 22-30 wks of age), TRAF-STOPS were able to halt atherosclerosis, resulting in a 〉 45% decrease in atherosclerotic plaque area. However, these SMIs had a low solubility, and had a half-life of only 8 hrs, and had to be injected daily. To improve the therapeutic applicability of our TRAF-STOPs, TRAF-STOP 6877002 was packed in HDL-based nanoparticles, and administered twice a week for 6 wks (wk 12-18) to ApoE-/- mice. The HDL-TRAF-STOP nanoparticles preferentially homed to macrophages, and the expression level in plaque macrophages was high. HDL-TRAF-STOP nanoparticle treatment reduced atherosclerosis by 42.6%. These newly developed, nanoparticle based CD40-TRAF6 inhibiting SMIs (TRAF-STOPs) are a promising lead for the development of therapeutics for the treatment of atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.376
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1494427-3
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