Cholesterol Loading Reprograms the MicroRNA-143/145–Myocardin Axis to Convert Aortic Smooth Muscle Cells to a Dysfunctional Macrophage-Like Phenotype
Open accessAbstract
Objective—: We previously showed that cholesterol loading in vitro converts mouse aortic vascular smooth muscle cells (VSMC) from a contractile state to one resembling macrophages. In human and mouse atherosclerotic plaques, it has become appreciated that ≈40% of cells classified as macrophages by histological markers may be of VSMC origin. Therefore, we sought to gain insight into the molecular regulation of this clinically relevant process. Approach and Results—: VSMC of mouse (or human) origin were incubated with cyclodextrin–cholesterol complexes for 72 hours, at which time the expression at the protein and mRNA levels of contractile-related proteins was reduced and of macrophage markers increased. Concurrent was downregulation of miR-143/145, which positively regulate the master VSMC differentiation transcription factor myocardin. Mechanisms were further probed in mouse VSMC. Maintaining the expression of myocardin or miR-143/145 prevented and reversed phenotypic changes caused by cholesterol loading. Reversal was also seen when cholesterol efflux was stimulated after loading. Notably, despite expression of macrophage markers, bioinformatic analyses showed that cholesterol-loaded cells remained closer to the VSMC state, consistent with impairment in classical macrophage functions of phagocytosis and efferocytosis. In apoE-deficient atherosclerotic plaques, cells positive for VSMC and macrophage markers were found lining the cholesterol-rich necrotic core. Conclusions—: Cholesterol loading of VSMC converts them to a macrophage-appearing state by downregulating the miR-143/145–myocardin axis. Although these cells would be classified by immunohistochemistry as macrophages in human and mouse plaques, their transcriptome and functional properties imply that their contributions to atherogenesis would not be those of classical macrophages.
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Decreased miR-145 leads to dedifferentiation of vascular smooth muscle cells and their increased phagocytic function.
“These changes lead to dedifferentiation of vascular smooth muscle cells and their increased phagocytic function [277].”
From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [277]
The Results sections on miR-143/145 and VSMC function report that cholesterol loading lowers both miRNAs, shifts VSMCs away from their contractile phenotype, and increases bead uptake relative to control VSMCs. The paper does not show that decreased miR-145 alone causes the increased phagocytosis; the cholesterol-loaded cells also remain much less phagocytic than macrophages. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMacrophage-like cells derived from vascular smooth muscle cells are distinct from classical monocyte-derived macrophages and dendritic cells.
“Interestingly, the macrophage-like cells derived from vascular smooth muscle cells are distinct from classical monocyte-derived macrophages and dendritic cells193.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [193]
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- Authors
- Vengrenyuk, Y., Nishi, H., Long, X., Ouimet, M., Savji, N., Martinez, F. O., Cassella, C. P., Moore, K. J., Ramsey, S. A., Miano, J. M., & Fisher, E. A.
- Affiliations
- Oregon State University (US)
- From the Marc and Ruti Bell Program in Vascular Biology, Division of Cardiology, Department of Medicine, NYU School of Medicine, New York (Y.V., H.N., M.O., N.S., C.P.C., K.J.M., E.A.F.); Center for Cardiovascular Sciences, Albany Medical College, NY (X.L.); Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom (F.O.M.); Department of Biomedical Sciences, Oregon State University, Corvallis (S.A.R.); and...
- Corresponding author
- Vengrenyuk, Yuliya
- Nishi, Hitoo
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2015-03
- Volume
- 35
- Issue
- 3
- Pages
- 535-546
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC4344402
- OpenAlex
- W2138463356
- Cited by
- 358
- References
- 49
- Citations by year
- 2026: 19 · 2025: 35 · 2024: 34 · 2023: 38 · 2022: 44 · 2021: 42 · 2020: 30 · 2019: 22 · 2018: 23 · 2017: 27 · 2016: 31 · 2015: 13
- FWCI
- 15.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Open Research (University of Surrey) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL084312, HL-084312, R01HL132574, HL-112793, HL098055, HL-117907, HL098807, K25HL098807, R01HL117907, R01HL117334, P01HL098055, HL108182, R01HL108182, R01HL112793, HL117334, T32HL098129)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- cholesterol loading, vascular smooth muscle cells, miR-143/145, myocardin, atherosclerosis, necrotic core, cholesterol efflux, phagocytosis, efferocytosis, atherosclerotic plaque, ApoE-deficient mice, contractile gene expression
- MeSH terms
- Myocardin, Animals, Aorta, Thoracic, Apolipoproteins E, Binding Sites, Cholesterol, Disease Models, Animal, Foam Cells, Gene Expression Regulation, Humans, Cholesterol, HDL, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Necrosis, Nuclear Proteins, Phagocytosis, Phenotype, Time Factors, Transfection, Signal Transduction, Trans-Activators, Mice, Knockout, Coculture Techniques, Cell Lineage, Jurkat Cells, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Myocytes, Smooth Muscle, MicroRNAs, Atherosclerosis, Sterol Regulatory Element Binding Protein 2, Cell Transdifferentiation, Plaque, Atherosclerotic
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