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PM 2.5 Induce Endothelial-Mesenchymal Transition and Cardiac Fibrosis via the NCOA4-Mediated Ferritinophagy.

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Titel: PM 2.5 Induce Endothelial-Mesenchymal Transition and Cardiac Fibrosis via the NCOA4-Mediated Ferritinophagy.
Autoren: Sun Q; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.; Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing, 100069, China., Wang M; Key Laboratory of Geographic Information Science of the Ministry of Education, School of Geographic Sciences, East China Normal University, Shanghai, 200241, China., Liu L; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China., Ding R; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.; Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing, 100069, China., Yan K; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.; Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing, 100069, China., Liu S; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.; Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing, 100069, China., Ren X; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.; Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing, 100069, China., Xu Q; Core Facilities for Electrophysiology, Core Facilities Center, Capital Medical University, Beijing, 100069, China., Sun Z; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.; Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing, 100069, China., Liu Q; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China., Yang Y; Key Laboratory of Geographic Information Science of the Ministry of Education, School of Geographic Sciences, East China Normal University, Shanghai, 200241, China., Duan J; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.; Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing, 100069, China.
Quelle: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2025 Dec; Vol. 12 (45), pp. e07536. Date of Electronic Publication: 2025 Sep 15.
Publikationsart: Journal Article
Sprache: English
Info zur Zeitschrift: Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE
Imprint Name(s): Original Publication: Weinheim : WILEY-VCH, [2014]-
MeSH-Schlagworte: Particulate Matter*/adverse effects , Particulate Matter*/toxicity , Nuclear Receptor Coactivators*/metabolism , Nuclear Receptor Coactivators*/genetics , Ferritins*/metabolism , Myocardium*/pathology , Myocardium*/metabolism , Epithelial-Mesenchymal Transition*/drug effects, Fibrosis/metabolism ; Animals ; Mice ; Humans ; Mice, Inbred C57BL ; Endothelial Cells/metabolism ; Endothelial Cells/drug effects ; Male ; Endothelial-Mesenchymal Transition
Abstract: Epidemiological evidence has indicated a strong association between fine particulate matter (PM 2.5 ) exposure and adverse cardiac outcomes, including dysfunction and fibrosis. However, the underlying mechanisms remain unclear. In this study, the chemical species-specific translocation of PM 2.5 is investigated to the heart and its associated toxicological mechanisms. It is found that PM 2.5 -derived iron (Fe)-containing particles, particularly magnetite, are specifically enriched in the hearts of mice, with Fe content in individual particles increasing progressively along the path from the lungs through serum to the heart. Notably, molecular dynamics simulations demonstrated that Fe-containing particles can form complexes with the key ferritinophagy regulator (nuclear receptor co-activator 4 [NCOA4]), thereby altering its structure and function. Further analyses confirmed that PM 2.5 upregulated NCOA4 expression in endothelial cells, which promoted the binding of transcription factor Kruppel-like factor 5 to transforming growth factor beta 1 promoter, driving endothelial-to-mesenchymal transition (EndMT) in vitro and in vivo. Additionally, PM 2.5 -treated endothelial cells facilitated the transformation of cardiac fibroblasts through paracrine signaling, leading to extracellular matrix production and cardiac fibrosis. Collectively, these findings reveal a previously unrecognized mechanism by which PM 2.5 -derived Fe-containing particles can trigger EndMT and cardiac fibrosis via ferritinophagy, with important implications for understanding the cardiovascular risks associated with air pollution.
(© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
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Grant Information: 2022YFA0806900 National Key R&D Program of China; 2023YFC3708302 National Key R&D Program of China; 82273659 National Natural Science Foundation of China; 42125102 National Natural Science Foundation of China; 22425041 National Natural Science Foundation of China; 22188102 National Natural Science Foundation of China; YSBR-086 Chinese Academy of Sciences Project for Young Scientists in Basic Research
Contributed Indexing: Keywords: air pollution; cardiac fibrosis; endothelial‐to‐mesenchymal transition; ferritinophagy; particulate matter
Substance Nomenclature: 0 (Particulate Matter)
0 (Nuclear Receptor Coactivators)
9007-73-2 (Ferritins)
0 (NCOA4 protein, human)
Entry Date(s): Date Created: 20250915 Date Completed: 20251204 Latest Revision: 20251206
Update Code: 20251206
PubMed Central ID: PMC12677608
DOI: 10.1002/advs.202507536
PMID: 40948359
Datenbank: MEDLINE
Beschreibung
Abstract:Epidemiological evidence has indicated a strong association between fine particulate matter (PM <subscript>2.5</subscript> ) exposure and adverse cardiac outcomes, including dysfunction and fibrosis. However, the underlying mechanisms remain unclear. In this study, the chemical species-specific translocation of PM <subscript>2.5</subscript> is investigated to the heart and its associated toxicological mechanisms. It is found that PM <subscript>2.5</subscript> -derived iron (Fe)-containing particles, particularly magnetite, are specifically enriched in the hearts of mice, with Fe content in individual particles increasing progressively along the path from the lungs through serum to the heart. Notably, molecular dynamics simulations demonstrated that Fe-containing particles can form complexes with the key ferritinophagy regulator (nuclear receptor co-activator 4 [NCOA4]), thereby altering its structure and function. Further analyses confirmed that PM <subscript>2.5</subscript> upregulated NCOA4 expression in endothelial cells, which promoted the binding of transcription factor Kruppel-like factor 5 to transforming growth factor beta 1 promoter, driving endothelial-to-mesenchymal transition (EndMT) in vitro and in vivo. Additionally, PM <subscript>2.5</subscript> -treated endothelial cells facilitated the transformation of cardiac fibroblasts through paracrine signaling, leading to extracellular matrix production and cardiac fibrosis. Collectively, these findings reveal a previously unrecognized mechanism by which PM <subscript>2.5</subscript> -derived Fe-containing particles can trigger EndMT and cardiac fibrosis via ferritinophagy, with important implications for understanding the cardiovascular risks associated with air pollution.<br /> (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
ISSN:2198-3844
DOI:10.1002/advs.202507536