{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:29:38Z","timestamp":1791462578737,"version":"4.3.4"},"reference-count":78,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,4,25]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Circulating monocytes largely contribute to macrophage buildup in atheromata, which is crucial for clearing subendothelial LDLs (low-density lipoproteins) and dead cells; however, the transitional trajectory from monocytes to macrophages in atherosclerotic plaques and the underlying regulatory mechanism remain unclear. Moreover, the role of alternative polyadenylation, a posttranscriptional regulator of cell fate, in monocyte\/macrophage fate decisions during atherogenesis is not entirely understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              To identify monocyte\/macrophage subtypes in atherosclerotic lesions and the effect of alternative polyadenylation on these subtypes and atherogenesis, single-cell RNA sequencing, 3\u2032-end sequencing, flow cytometric, and histopathologic analyses were performed on plaques obtained from\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mouse arteries with or without myeloid deletion of\n              <jats:italic>Srsf3<\/jats:italic>\n              (serine\/arginine-rich splicing factor 3). Cell fractionation, polysome profiling, L-azidohomoalanine metabolic labeling assay, and metabolomic profiling were conducted to disclose the underlying mechanisms. Reprogramming of widespread alternative polyadenylation patterns was estimated in human plaques via bulk RNA sequencing.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We identified a subset of lesional cells in a monocyte-to-macrophage transitional state, which exhibited high expression of chemokines in mice.\n              <jats:italic>Srsf3<\/jats:italic>\n              deletion caused a maturation delay of these transitional cells and phagocytic impairment of lesional macrophages, aggravating atherosclerosis. Mechanistically,\n              <jats:italic>Srsf3<\/jats:italic>\n              deficiency shortened 3\u2032 untranslated regions of mitochondria-associated Aars2 (alanyl-tRNA synthetase 2), disrupting its translation. The resultant impairment of protein synthesis in mitochondria led to mitochondrial dysfunction with declined NAD\n              <jats:sup>+<\/jats:sup>\n              (nicotinamide adenine dinucleotide, oxidized form) levels, activation of the integrated stress response, and metabolic reprogramming in macrophages. Administering an NAD\n              <jats:sup>+<\/jats:sup>\n              precursor nicotinamide mononucleotide or the integrated stress response inhibitor partially restored\n              <jats:italic>Srsf3<\/jats:italic>\n              -deficient macrophage maturation, and nicotinamide mononucleotide treatment mitigated the proatherosclerotic effects of\n              <jats:italic>Srsf3<\/jats:italic>\n              deficiency. Consistently,\n              <jats:italic>Srsf3<\/jats:italic>\n              downregulation, global 3\u2032 untranslated region shortening, and accumulation of these transitional macrophages were associated with atherosclerosis progression in humans.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Our study reveals that Srsf3-dependent generation of long 3\u2032 untranslated region is required for efficient mitochondrial translation, which promotes mature phagocytic macrophage formation, thereby playing a protective role in atherosclerosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.326111","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T10:47:38Z","timestamp":1743418058000},"page":"985-1009","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Srsf3-Dependent APA 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Y.T., J.Y., Y.J., Y.X., L.C., S.C., L.W., Y.Q., Y.W.), Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, and Department of Rheumatology, Zhongshan Hospital (X.Y., X.Z., Y.T., J.Y., Y.J., Y.X., L.C., S.C., L.W., Y.Q., Y.W.), Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8019-1585","authenticated-orcid":true,"given":"Yunhui","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, and Department of Rheumatology, Zhongshan Hospital (X.Y., X.Z., Y.T., J.Y., Y.J., Y.X., L.C., S.C., L.W., Y.Q., Y.W.), Fudan University, Shanghai, 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