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      Inflammation: A Novel Therapeutic Target/Direction in Atherosclerosis

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          Abstract

          Over the past two decades, the viewpoint of atherosclerosis has been replaced gradually by a lipid-driven, chronic, low-grade inflammatory disease of the arterial wall. Current treatment of atherosclerosis is focused on limiting its risk factors, such as hyperlipidemia or hypertension. However, treatment targeting the inflammatory nature of atherosclerosis is still very limited and deserves further attention to fight atherosclerosis successfully. Here, we review the current development of inflammation and atherosclerosis to discuss novel insights and potential targets in atherosclerosis, and to address drug discovery based on anti-inflammatory strategy in atherosclerotic disease.

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          Targeting Toll-like receptors: emerging therapeutics?

          Elizabeth J Hennessy, Andrew Parker, Luke A J O'Neill (2010)
          There is a growing interest in the targeting of Toll-like receptors (TLRs) for the prevention and treatment of cancer, rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus (SLE). Several new compounds are now undergoing preclinical and clinical evaluation, with a particular focus on TLR7 and TLR9 activators as adjuvants in infection and cancer, and inhibitors of TLR2, TLR4, TLR7 and TLR9 for the treatment of sepsis and inflammatory diseases. Here, we focus on TLRs that hold the most promise for drug discovery research, highlighting agents that are in the discovery phase and in clinical trials,and on the emerging new aspects of TLR-mediated signalling - such as control by ubiquitination and regulation by microRNAs - that might offer further possibilities of therapeutic manipulation.
          Article 0 comments Cited 273 times – based on 0 reviews     Review now
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            Therapeutic siRNA silencing in inflammatory monocytes

            Florian Leuschner, Partha Dutta, Rostic Gorbatov … (2011)
            Inflammatory monocytes -- but not the non-inflammatory subset -- depend on the chemokine receptor CCR2 for distribution to injured tissue and stimulate disease progression. Precise therapeutic targeting of this inflammatory monocyte subset could spare innate immunity's essential functions for maintenance of homeostasis and thus limit unwanted effects. Here we developed siRNA nanoparticles targeting CCR2 expression in inflammatory monocytes. We identified an optimized lipid nanoparticle and silencing siRNA sequence that when administered systemically, had rapid blood clearance, accumulated in spleen and bone marrow and showed high cellular localization of fluorescently tagged siRNA inside monocytes. Efficient degradation of CCR2 mRNA in monocytes prevented their accumulation in sites of inflammation. Specifically, the treatment attenuated their number in atherosclerotic plaques, reduced infarct size following coronary artery occlusion, prolonged normoglycemia in diabetic mice after pancreatic islet transplantation and resulted in reduced tumor volumes and lower numbers of tumor-associated macrophages. Taken together, siRNA nanoparticle-mediated CCR2 gene silencing in leukocytes selectively modulates functions of innate immune cell subtypes and may allow for the development of specific anti-inflammatory therapy.
            Article 0 comments Cited 268 times – based on 0 reviews     Review now
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              Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes.

              Siroon Bekkering, Jessica Quintin, Leo Joosten … (2014)
              Although the role of monocytes in the pathogenesis of atherosclerosis is well established, the persistent vascular inflammation remains largely unexplained. Recently, our group reported that stimulation of monocytes with various microbial products can induce a long-lasting proinflammatory phenotype via epigenetic reprogramming, a process termed trained immunity. We now hypothesize that oxidized low-density lipoprotein (oxLDL) also induces a long-lasting proinflammatory phenotype in monocytes, which accelerates atherosclerosis by proinflammatory cytokine production and foam cell formation. Isolated human monocytes were exposed for 24 hours to medium or oxLDL. After washing and resting for 6 days, the cells were exposed to toll-like receptor 2 and 4 agonists. Pre-exposure to oxLDL increased mRNA expression and protein formation on toll-like receptor 2 and 4 stimulation of several proatherogenic proteins, including interleukin-6, interleukin-18, interleukin-8, tumor necrosis factor-α, monocyte chemoattractant protein 1, and matrix metalloproteinase 2 and 9. In addition, foam cell formation was enhanced after oxLDL exposure, which was associated with an upregulation of scavenger receptors CD36 and scavenger receptor-A and downregulation of ATP-binding cassette transporters, ABCA1 and ABCG1. Chromatin immunoprecipitation performed 6 days after oxLDL stimulation demonstrated increased trimethylation of lysine 4 at histone 3 in promoter regions of tnfα, il-6, il-18, mcp-1, mmp2, mmp9, cd36, and sr-a. Finally, pretreatment of the monocytes with the histone methyltransferase inhibitor methylthioadenosine completely prevented the oxLDL-induced long-lasting proinflammatory phenotype. Brief exposure of monocytes to a low concentration of oxLDL induces a long-lasting proatherogenic macrophage phenotype via epigenetic histone modifications, characterized by increased proinflammatory cytokine production and foam cell formation. © 2014 American Heart Association, Inc.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Curr Pharm Des
                Journal ID (iso-abbrev): Curr. Pharm. Des
                Journal ID (publisher-id): CPD
                Title: Current Pharmaceutical Design
                Publisher: Bentham Science Publishers
                ISSN (Print): 1381-6128
                ISSN (Electronic): 1873-4286
                Publication date (Electronic): March 2017
                Publication date (Print): March 2017
                Volume: 23
                Issue: 8
                Pages: 1216-1227
                Affiliations
                Department of Pharmacology, College of Pharmacy, Third Military Medical University , Chongqing, 400038 , China; Assisted 
Reproductive Center, The First Affiliated Hospital, Chongqing Medical University , Chongqing, 400016 , China
                Author notes
                [* ]Address correspondence to this author at the Department of Pharmacology, College of Pharamacy, The Third Military Medical University, P.O. Box: 400038, Chongqing, China; Tel/Fax: +86-23-68752266; E-mail: zhouh64@ 123456163.com
                Article
                Publisher ID: CPD-23-1216
                DOI: 10.2174/1381612822666161230142931
                PMC ID: 6302344
                PubMed ID: 28034355
                SO-VID: 107b674b-48d2-4b2a-9137-4a52632be61c
                Copyright © © 2017 Bentham Science Publishers
                License:

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                Date received : 15 August 2016
                Date accepted : 27 December 2016
                Categories
                Subject: Article

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: atherosclerosis,inflammation,drug discovery,target identification
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: atherosclerosis, inflammation, drug discovery, target identification

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