Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4
Introduction: Exosome-miR-146a is significantly increased in patients with Atherosclerosis (AS), but its mechanism and effect on AS have not been fully elucidated. Objectives: To explore the change rule and mechanism of exosomes release, and the role and molecular mechanism of exosome-miR-146a in AS...
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Elsevier
2025-07-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123224003552 |
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| author | Kefeng Zhai Liangle Deng Yuxuan Wu Han Li Jing Zhou Ying Shi Jianhu Jia Wei Wang Sihui Nian Ghulam Jilany Khan Hesham R. El-Seedi Hong Duan Lili Li Zhaojun Wei |
| author_facet | Kefeng Zhai Liangle Deng Yuxuan Wu Han Li Jing Zhou Ying Shi Jianhu Jia Wei Wang Sihui Nian Ghulam Jilany Khan Hesham R. El-Seedi Hong Duan Lili Li Zhaojun Wei |
| author_sort | Kefeng Zhai |
| collection | DOAJ |
| description | Introduction: Exosome-miR-146a is significantly increased in patients with Atherosclerosis (AS), but its mechanism and effect on AS have not been fully elucidated. Objectives: To explore the change rule and mechanism of exosomes release, and the role and molecular mechanism of exosome-miR-146a in AS. Methods: We isolated and identified exosomes from THP-1 macrophages after treating them with ox-LDL. Then used co-immunoprecipitation and silver staining to identify the proteins involved in regulating exosome release. PKH67 was used to label exosomes to confirm that cells can absorb them, and then co-culture with HVSMCs for cell proliferation and migration detection. The target genes of miR-146a were screened and identified through bioinformatics and luciferase activity assay, and the expression of miR-146a and related proteins was detected through qRT-PCR and Western blot in HUVECs. An AS model in LDLR-/- mice induced by a high-fat diet was developed to investigate the impact of exosome-miR-146a on AS. Results: The results showed that experimental foam cells from AS showed higher expression of miR-146a. It was observed that NMMHC IIA and HSP70 interacted to regulate the release of exosomes. And HUVECs can absorb exosomes derived from macrophages. In addition, we also found that miR-146a directly targeted the SMAD4 gene to modulate the p38 MAPK signaling pathway, thereby mediating HUVECs damage. Furthermore, exosome-miR-146a induced abnormal proliferation and migration of HVSMCs. The expression of miR-146a was significantly reduced in miR-146a-mimics mice and increased in miR-146a inhibitor mice whereas the inhibition of miR-146a effectively reduced while increasing miR-146a worsened AS in mice. Conclusion: Our findings expressed the potential of miR-146a as a favorable therapeutic target for AS, however, further exploration is suggestive for deep understanding of the mechanisms regulating exosome-miR-146a release in vivo and to develop effective therapeutic strategies involving miR-146a. |
| format | Article |
| id | doaj-art-4c9b2f6be6e5457091d34871eacf28d5 |
| institution | Kabale University |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
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| series | Journal of Advanced Research |
| spelling | doaj-art-4c9b2f6be6e5457091d34871eacf28d52025-08-20T03:47:16ZengElsevierJournal of Advanced Research2090-12322025-07-017372974110.1016/j.jare.2024.08.012Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4Kefeng Zhai0Liangle Deng1Yuxuan Wu2Han Li3Jing Zhou4Ying Shi5Jianhu Jia6Wei Wang7Sihui Nian8Ghulam Jilany Khan9Hesham R. El-Seedi10Hong Duan11Lili Li12Zhaojun Wei13School of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, China; College of Biological and Food Engineering, Anhui Polytechnic University, Wuhu, Anhui 241000, China; General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou 234000, ChinaSchool of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, ChinaSchool of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, ChinaSchool of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, China; College of Biological and Food Engineering, Anhui Polytechnic University, Wuhu, Anhui 241000, ChinaSchool of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, China; College of Biological and Food Engineering, Anhui Polytechnic University, Wuhu, Anhui 241000, ChinaSchool of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, China; College of Biological and Food Engineering, Anhui Polytechnic University, Wuhu, Anhui 241000, ChinaSchool of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, ChinaSchool of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, China; Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo-Ourense Campus, Ourense E-32004, SpainSchool of Pharmacy, Wannan Medical College, Wuhu, Anhui 241002, ChinaDepartment of Pharmacology and Therapeutics, Faculty of Pharmacy, University of Central Punjab, Lahore 54000, PakistanInternational Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China; Department of Chemistry, Faculty of Science, Islamic University of Madinah, Madinah 42351, Saudi ArabiaSchool of Biological and Food Engineering, Engineering Research Center for Development and High Value Utilization of Genuine Medicinal Materials in North Anhui Province, Suzhou University, Suzhou, Anhui 234000, China; College of Biological and Food Engineering, Anhui Polytechnic University, Wuhu, Anhui 241000, China; Corresponding authors.General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou 234000, China; Corresponding authors.School of Biological Science and Engineering, North Minzu University, Yinchuan 750021, China; Corresponding authors.Introduction: Exosome-miR-146a is significantly increased in patients with Atherosclerosis (AS), but its mechanism and effect on AS have not been fully elucidated. Objectives: To explore the change rule and mechanism of exosomes release, and the role and molecular mechanism of exosome-miR-146a in AS. Methods: We isolated and identified exosomes from THP-1 macrophages after treating them with ox-LDL. Then used co-immunoprecipitation and silver staining to identify the proteins involved in regulating exosome release. PKH67 was used to label exosomes to confirm that cells can absorb them, and then co-culture with HVSMCs for cell proliferation and migration detection. The target genes of miR-146a were screened and identified through bioinformatics and luciferase activity assay, and the expression of miR-146a and related proteins was detected through qRT-PCR and Western blot in HUVECs. An AS model in LDLR-/- mice induced by a high-fat diet was developed to investigate the impact of exosome-miR-146a on AS. Results: The results showed that experimental foam cells from AS showed higher expression of miR-146a. It was observed that NMMHC IIA and HSP70 interacted to regulate the release of exosomes. And HUVECs can absorb exosomes derived from macrophages. In addition, we also found that miR-146a directly targeted the SMAD4 gene to modulate the p38 MAPK signaling pathway, thereby mediating HUVECs damage. Furthermore, exosome-miR-146a induced abnormal proliferation and migration of HVSMCs. The expression of miR-146a was significantly reduced in miR-146a-mimics mice and increased in miR-146a inhibitor mice whereas the inhibition of miR-146a effectively reduced while increasing miR-146a worsened AS in mice. Conclusion: Our findings expressed the potential of miR-146a as a favorable therapeutic target for AS, however, further exploration is suggestive for deep understanding of the mechanisms regulating exosome-miR-146a release in vivo and to develop effective therapeutic strategies involving miR-146a.http://www.sciencedirect.com/science/article/pii/S2090123224003552exosome-miR-146aSMAD4Foam cellsAtherosclerosisNMMHC II A |
| spellingShingle | Kefeng Zhai Liangle Deng Yuxuan Wu Han Li Jing Zhou Ying Shi Jianhu Jia Wei Wang Sihui Nian Ghulam Jilany Khan Hesham R. El-Seedi Hong Duan Lili Li Zhaojun Wei Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4 Journal of Advanced Research exosome-miR-146a SMAD4 Foam cells Atherosclerosis NMMHC II A |
| title | Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4 |
| title_full | Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4 |
| title_fullStr | Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4 |
| title_full_unstemmed | Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4 |
| title_short | Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4 |
| title_sort | extracellular vesicle derived mir 146a as a novel crosstalk mechanism for high fat induced atherosclerosis by targeting smad4 |
| topic | exosome-miR-146a SMAD4 Foam cells Atherosclerosis NMMHC II A |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224003552 |
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