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      Radiation‐induced myocardial fibrosis: Mechanisms underlying its pathogenesis and therapeutic strategies

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          Abstract

          Radiation‐induced myocardial fibrosis (RIMF) is a potentially lethal clinical complication of chest radiotherapy (RT) and a final stage of radiation‐induced heart disease (RIHD). RIMF is characterized by decreased ventricular elasticity and distensibility, which can result in decreased ejection fraction, heart failure and even sudden cardiac death. Together, these conditions impair the long‐term health of post‐RT survivors and limit the dose and intensity of RT required to effectively kill tumour cells. Although the exact mechanisms involving in RIMF are unclear, increasing evidence indicates that the occurrence of RIMF is related to various cells, regulatory molecules and cytokines. However, accurately diagnosing and identifying patients who may progress to RIMF has been challenging. Despite the urgent need for an effective treatment, there is currently no medical therapy for RIMF approved for routine clinical application. In this review, we investigated the underlying pathophysiology involved in the initiation and progression of RIMF before outlining potential preventative and therapeutic strategies to counter this toxicity.

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          Most cited references113

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          Cardiac Fibrosis: The Fibroblast Awakens.

          Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.
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            Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis.

            The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β-Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.
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              Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines.

              Cardiovascular (CV) toxicity is a potential short- or long-term complication of various anticancer therapies. Some drugs, such as anthracyclines or other biological agents, have been implicated in causing potentially irreversible clinically important cardiac dysfunction. Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy agents, rare but serious complications have been described, and longer follow-up is needed to determine the exact profile and outcomes of related cardiac side-effects. Some of these side-effects are irreversible, leading to progressive CV disease, and some others induce reversible dysfunction with no long-term cardiac damage to the patient. Assessment of the prevalence, type and severity of cardiac toxicity caused by various cancer treatments is a breakthrough topic for patient management. Guidelines for preventing, monitoring and treating cardiac side-effects are a major medical need. Efforts are needed to promote strategies for cardiac risk prevention, detection and management, avoiding unintended consequences that can impede development, regulatory approval and patient access to novel therapy. These new ESMO Clinical Practice Guidelines are the result of a multidisciplinary cardio-oncology review of current evidence with the ultimate goal of providing strict criteria-based recommendations on CV risk prevention, assessment, monitoring and management during anticancer treatment.
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                Author and article information

                Contributors
                xiny@jlu.edu.cn
                jiangx@jlu.edu.cn
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                14 June 2020
                July 2020
                : 24
                : 14 ( doiID: 10.1111/jcmm.v24.14 )
                : 7717-7729
                Affiliations
                [ 1 ] Department of Radiation Oncology The First Hospital of Jilin University Changchun China
                [ 2 ] Jilin Provincial Key Laboratory of Radiation Oncology & Therapy The First Hospital of Jilin University Changchun China
                [ 3 ] NHC Key Laboratory of Radiobiology School of Public Health Jilin University Changchun China
                [ 4 ] Phase I Clinical Research Center The First Hospital of Jilin University Changchun China
                [ 5 ] Department of Biology Valencia College Orlando FL USA
                [ 6 ] Key Laboratory of Pathobiology Ministry of Education Jilin University Changchun China
                Author notes
                [*] [* ] Correspondenc

                Ying Xin, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, 126 Xinmin Street, Changchun 130021, China.

                Email: xiny@ 123456jlu.edu.cn

                Xin Jiang, Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China.

                Email: jiangx@ 123456jlu.edu.cn

                Author information
                https://orcid.org/0000-0002-4613-7438
                Article
                JCMM15479
                10.1111/jcmm.15479
                7348163
                32536032
                7582dc7b-5642-4946-984b-5016d836e92d
                © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 February 2020
                : 18 April 2020
                : 24 May 2020
                Page count
                Figures: 1, Tables: 1, Pages: 13, Words: 10219
                Funding
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81570344
                Funded by: Jilin University , open-funder-registry 10.13039/501100004032;
                Award ID: 2015225
                Award ID: 2015203
                Funded by: National Key R&D Program of China
                Award ID: 2017YFC0112100
                Funded by: Jilin Provincial Science and Technology Foundations
                Award ID: 20180414039GH
                Award ID: 20190201200JC
                Categories
                Review Article
                Reviews
                Custom metadata
                2.0
                July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:10.07.2020

                Molecular medicine
                micro‐rnas,radiation‐induced myocardial fibrosis,reactive oxygen species,therapeutic strategies,transforming growth factor β1

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