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Alternatively, activated macrophages are involved in the development of fibrosis and tissue remodeling. Although the receptor for advanced glycation end products (RAGE) is involved in MF, its potential role in regulating macrophage function in cardiac fibrosis has not been fully investigated. We aimed to determine the role of macrophage RAGE in transverse aortic constriction (TAC)\u2010induced MF. In this study, we found that RAGE expression was markedly increased in the infiltrated alternatively activated macrophages within mice hearts after TAC. RAGE knockout mice showed less infiltration of alternatively activated macrophages and attenuated cardiac hypertrophy and fibrosis compared to the wild\u2010type mice. Our data suggest that mice with macrophage\u2010specific genetic deletion of RAGE were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload, which led to a decreased proportion of alternatively activated macrophages in heart tissues. Our in\u00a0vitro experiments demonstrated that RAGE deficiency inhibited the differentiation into alternatively activated macrophages by suppressing autophagy activation. In the co\u2010culture system, in\u00a0vitro polarization of RAW264.7 macrophages toward an alternatively activated phenotype stimulated the expression of \u03b1\u2010smooth muscle actin and collagen in cardiac fibroblasts. However, the knockdown of RAGE and inhibition of autophagy in macrophages showed reduced fibroblast\u2010to\u2010myofibroblast transition (FMT). Collectively, our results suggest that RAGE plays an important role in the recruitment and activation of alternatively activated macrophages by regulating autophagy, which contributes to MF. Thus, blockage of RAGE signaling may be an attractive therapeutic target for the treatment of hypertensive heart disease.<\/jats:p>","DOI":"10.1096\/fj.202300173rr","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T10:25:43Z","timestamp":1697711143000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Macrophage\n                    <scp>RAGE<\/scp>\n                    deficiency prevents myocardial fibrosis by repressing autophagy\u2010mediated macrophage alternative activation"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8950-5827","authenticated-orcid":false,"given":"Jiaqi","family":"He","sequence":"first","affiliation":[{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine  Guangzhou China"},{"name":"Lingnan Medical Research Center Guangdong 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