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      Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis

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          Abstract

          Inflammation is a hallmark and potent driver of pathological vascular remodelling in atherosclerosis. However, current anti-inflammatory therapeutic strategies have shown mixed results. As an alternative perspective on the conundrum of chronic inflammation emerging evidence points towards a small subset of senescent cells as a critical player and central node driving atherosclerosis. Senescent cells belonging to various cell types are a dominant and chronic source of a large array of pro-inflammatory cytokines and various additional plaque destabilizing factors, being involved with various aspects of atherosclerosis pathogenesis. Antagonizing these key agitators of local chronic inflammation and plaque instability may provide a causative and multi-purpose therapeutic strategy to treat atherosclerosis. Anti-senescence treatment options with translational potential are currently in development. However, several questions and challenges remain to be addressed before these novel treatment approaches may enter the clinical setting.

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          Most cited references158

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          Cellular senescence in aging and age-related disease: from mechanisms to therapy.

          Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy.
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            The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

            The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1 −/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1 −/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
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              Inflammation in atherosclerosis: from pathophysiology to practice.

              Until recently, most envisaged atherosclerosis as a bland arterial collection of cholesterol, complicated by smooth muscle cell accumulation. According to that concept, endothelial denuding injury led to platelet aggregation and release of platelet factors which would trigger the proliferation of smooth muscle cells in the arterial intima. These cells would then elaborate an extracellular matrix that would entrap lipoproteins, forming the nidus of the atherosclerotic plaque. Beyond the vascular smooth muscle cells long recognized in atherosclerotic lesions, subsequent investigations identified immune cells and mediators at work in atheromata, implicating inflammation in this disease. Multiple independent pathways of evidence now pinpoint inflammation as a key regulatory process that links multiple risk factors for atherosclerosis and its complications with altered arterial biology. Knowledge has burgeoned regarding the operation of both innate and adaptive arms of immunity in atherogenesis, their interplay, and the balance of stimulatory and inhibitory pathways that regulate their participation in atheroma formation and complication. This revolution in our thinking about the pathophysiology of atherosclerosis has now begun to provide clinical insight and practical tools that may aid patient management. This review provides an update of the role of inflammation in atherogenesis and highlights how translation of these advances in basic science promises to change clinical practice.
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                Author and article information

                Journal
                Eur Heart J
                Eur. Heart J
                eurheartj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                14 August 2020
                03 January 2020
                03 January 2020
                : 41
                : 31 , Focus Issue on Inflammation
                : 2983-2996
                Affiliations
                [1 ] Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School , Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
                [2 ] Department of Cardiology and Angiology, Hannover Medical School , Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
                [3 ] Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Martin-Luther-University Halle (Saale) , Ernst-Grube-Strasse 40, 06120 Halle (Saale), Germany
                Author notes
                Corresponding author. Tel: +49 511 532 5272, Fax: +49 511 532 5274, Email: Thum.Thomas@ 123456mh-hannover.de ; Tel: +49 345 557-2601, Fax: +49 345 5572072, Email: Daniel.Sedding@ 123456uk-halle.de
                Author information
                http://orcid.org/0000-0002-6285-9721
                http://orcid.org/0000-0002-8855-2883
                http://orcid.org/0000-0003-4360-1511
                http://orcid.org/0000-0001-7312-5216
                Article
                ehz919
                10.1093/eurheartj/ehz919
                7453834
                31898722
                41b08161-0557-4d03-b8de-e2f90ce6516c
                © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 22 June 2019
                : 13 September 2019
                : 12 December 2019
                Page count
                Pages: 14
                Funding
                Funded by: Deutsche Forschungsgemeinschaft, DOI 10.13039/501100001659;
                Award ID: KFO FOR311-2
                Award ID: TH903/20-1
                Funded by: Cluster of Excellence REBIRTH;
                Funded by: Regenerative Biology to Reconstructive Therapy EXC 62;
                Funded by: German Academic Exchange Service Graduate School Scholarship Programme;
                Award ID: 57320205
                Funded by: Foundation Leducq;
                Categories
                Clinical Reviews
                Vascular Medicine
                AcademicSubjects/MED00200

                Cardiovascular Medicine
                atherosclerosis,inflammation,ageing,cardiovascular disease,vascular disease

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