MicroRNA-26b-/- augments atherosclerosis, while mimic-loaded nanoparticles reduce atherogenesis.
| Title: | MicroRNA-26b-/- augments atherosclerosis, while mimic-loaded nanoparticles reduce atherogenesis. |
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| Authors: | Peters LJF; Institute for Cardiovascular Prevention (IPEK), LMU Munich, 80336 Munich, Germany.; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Bidzhekov K; Institute for Cardiovascular Prevention (IPEK), LMU Munich, 80336 Munich, Germany.; Bonnin-Marquez A; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Pauwelsstrasse 17, Aachen 52074, Germany.; Sundararaman SS; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Huchzermeier R; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Pauwelsstrasse 17, Aachen 52074, Germany.; Maas SL; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Pauwelsstrasse 17, Aachen 52074, Germany.; Abschlag K; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Pauwelsstrasse 17, Aachen 52074, Germany.; Jans A; Department of Medicine III, University Hospital Aachen, Aachen 52074, Germany.; Lin C; Department of Medicine III, University Hospital Aachen, Aachen 52074, Germany.; Haberbosch M; Institute for Cardiovascular Prevention (IPEK), LMU Munich, 80336 Munich, Germany.; Jansen Y; Institute for Cardiovascular Prevention (IPEK), LMU Munich, 80336 Munich, Germany.; Yu B; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht 6229 ER, The Netherlands.; Sluimer JC; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht 6229 ER, The Netherlands.; Department for Renal and Hypertensive, Rheumatological and Immunological Diseases (Medical Clinic II), RWTH Aachen, 52074 Aachen, Germany.; BHF Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.; Gijbels MJ; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht 6229 ER, The Netherlands.; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences: Atherosclerosis & Ischemic Syndrome; Amsterdam Infection and Immunity: Inflammatory Diseases; Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.; Jankowski J; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Pauwelsstrasse 17, Aachen 52074, Germany.; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht 6229 ER, The Netherlands.; Bartneck M; Department of Medicine III, University Hospital Aachen, Aachen 52074, Germany.; DWI-Leibniz Institute for Interactive Materials, Aachen 52074, Germany.; Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany.; Biessen EAL; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Pauwelsstrasse 17, Aachen 52074, Germany.; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht 6229 ER, The Netherlands.; Weber C; Institute for Cardiovascular Prevention (IPEK), LMU Munich, 80336 Munich, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich 80337, Germany.; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht 6200, The Netherlands.; Munich Cluster for Systems Neurology (SyNergy), Munich 81377, Germany.; Döring Y; Institute for Cardiovascular Prevention (IPEK), LMU Munich, 80336 Munich, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich 80337, Germany.; Swiss Cardiovascular Center, Division of Angiology, Inselspital, Bern University Hospital, University of Bern, Bern CH-3010, Switzerland.; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.; van der Vorst EPC; Institute for Cardiovascular Prevention (IPEK), LMU Munich, 80336 Munich, Germany.; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany.; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Pauwelsstrasse 17, Aachen 52074, Germany.; Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany. |
| Source: | Cardiovascular research [Cardiovasc Res] 2025 Dec 31; Vol. 121 (17), pp. 2700-2713. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Oxford Journals Country of Publication: England NLM ID: 0077427 Publication Model: Print Cited Medium: Internet ISSN: 1755-3245 (Electronic) Linking ISSN: 00086363 NLM ISO Abbreviation: Cardiovasc Res Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2008- : Oxford : Oxford Journals; Original Publication: London, British Medical Assn. |
| MeSH Terms: | MicroRNAs*/genetics ; MicroRNAs*/metabolism ; Atherosclerosis*/metabolism ; Atherosclerosis*/genetics ; Atherosclerosis*/pathology ; Atherosclerosis*/prevention & control ; Macrophages*/metabolism ; Macrophages*/pathology ; Aortic Diseases*/metabolism ; Aortic Diseases*/pathology ; Aortic Diseases*/genetics ; Aortic Diseases*/prevention & control ; Aorta*/metabolism ; Aorta*/pathology ; Aorta, Thoracic*/metabolism ; Aorta, Thoracic*/pathology ; Plaque, Atherosclerotic* ; Nanoparticles*; Apolipoproteins E/genetics ; Apolipoproteins E/deficiency ; Animals ; Disease Models, Animal ; Mice, Knockout, ApoE ; Mice, Inbred C57BL ; Cells, Cultured ; Male ; Phenotype ; Diet, Western ; Mice ; Liposomes |
| Abstract: | Aims: Increasing evidence has shown that microRNAs (miRs) play a fundamental role in atherosclerosis, but the exact role of various miRs remains elusive. Preliminary data showed that, with a five-fold increase, miR-26b was highly expressed in human atherosclerotic plaques compared to healthy vessels. Therefore, we aimed to determine its cell-specific effects on atherosclerosis development and its therapeutic potential.; Methods and Results: We examined the role of miR-26b in atherosclerosis by using whole-body Apoe-/-Mir26b-/- and myeloid cell-specific miR-26b-deficient (LysM-Cre) mice on a Western-type diet (WTD). Atherosclerotic plaque size and phenotype, as well as the phenotype and function of bone marrow-derived macrophages (BMDMs) from Apoe-/-Mir26b-/- mice, were investigated. Lipid nanoparticles (LNPs) served as vehicles for miR-26b mimics to restore miR-26b levels in miR-26b-deficient BMDMs in vitro and in mice in vivo. Apoe-/-Mir26b-/- mice have a striking 2.8-fold increase in atherosclerotic lesion size in the aortic arch after 12-week WTD, compared to control Apoe-/-, while lesions in the aortic root were unaffected. Consistent with a more advanced plaque phenotype, collagen, smooth muscle cell, and necrotic core content were all significantly increased in plaques from Apoe-/-Mir26b-/- mice, whilst the relative macrophage content was significantly reduced. This phenotype could also be observed in Apoe-/-Mir26b-/- mice after 4-week WTD. Intriguingly, relative plaque size in the arches of Apoe-/-LysmCre+Mir26bfl/fl mice was increased by 2.5-fold, suggesting a role for myeloid-specific miR-26b in atherosclerosis development. Further highlighting its myeloid-specific effects, Apoe-/-Mir26b-/- BMDMs showed an increase in pro-inflammatory cytokine secretion, which could be rescued by LNPs containing miR-26b mimics. MiR-26b pull-down analysis revealed AnnexinA2 as one of the novel targets playing a key role in these effects, which could be validated in BMDMs in vitro. Furthermore, in vivo treatment of Apoe-/-Mir26b-/- mice as well as ex vivo treatment of human plaques with miR-26b-mimic-loaded LNPs demonstrated their therapeutic potential and human relevance, respectively.; Conclusion: Overall, our results clearly demonstrate an atheroprotective role of miR-26b by attenuating lesion formation, mainly by suppressing inflammation and stimulating collagen breakdown. Furthermore, the therapeutic potential of miR-26b mimic-loaded LNPs could be proven, opening up new avenues for miRNA-based treatment options in the future.; (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.) |
| Competing Interests: | Conflict of interest. The authors declare no conflict of interest. |
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| Grant Information: | Interdisciplinary Center for Clinical Research; RWTH Aachen University; SFB TRR219 Deutsche Forschungsgemeinschaft; 322900939 Deutsche Forschungsgemeinschaft; M07 Deutsche Forschungsgemeinschaft; S199/10084/2021 Corona Foundation; Chinese Scholarship council; VIDI #91718364 Netherlands organization for scientific research; ASPASIA #015.013.064 Netherlands organization for scientific research |
| Contributed Indexing: | Keywords: Atherosclerosis; Lipid nanoparticles; Macrophages; MicroRNA-26b |
| Substance Nomenclature: | 0 (MicroRNAs); 0 (Mirn26 microRNA, mouse); 0 (Lipid Nanoparticles); 0 (Apolipoproteins E); 0 (Apoe protein, mouse); 0 (Liposomes) |
| Entry Date(s): | Date Created: 20251112 Date Completed: 20251231 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12754845 |
| DOI: | 10.1093/cvr/cvaf234 |
| PMID: | 41223017 |
| Database: | MEDLINE |
Journal Article