Contribution of Intimal Smooth Muscle Cells to Cholesterol Accumulation and Macrophage-Like Cells in Human Atherosclerosis
Abstract
Background—: Intimal smooth muscle cells (SMCs) contribute to the foam cell population in arterial plaque, and express lower levels of the cholesterol exporter ATP-binding cassette transporter A1 (ABCA1) in comparison with medial arterial SMCs. The relative contribution of SMCs to the total foam cell population and their expression of ABCA1 in comparison with intimal monocyte-derived macrophages, however, are unknown. Although the expression of macrophage markers by SMCs following lipid loading has been described, the relevance of this phenotypic switch by SMCs in human coronary atherosclerosis has not been determined. Methods and Results—: Human coronary artery sections from hearts explanted at the time of transplantation were processed to clearly delineate intracellular and extracellular lipids and allow costaining for cell-specific markers. Costaining for oil red O and the SMC-specific marker SM α-actin of foam cell–rich lesions revealed that 50±7% (average±standard error of the mean, n=14 subjects) of total foam cells were SMC derived. ABCA1 expression by intimal SMCs was significantly reduced between early and advanced atherosclerotic lesions, with no loss in ABCA1 expression by myeloid lineage cells. Costaining with the macrophage marker CD68 and SM α-actin revealed that 40±6% (n=15) of CD68-positive cells originated as SMCs in advanced human coronary atherosclerosis. Conclusions—: These findings suggest SMCs contain a much larger burden of the excess cholesterol in human coronary atherosclerosis than previously known, in part, because of their relative inability to release excess cholesterol via ABCA1 in comparison with myeloid lineage cells. Our results also indicate that many cells identified as monocyte-derived macrophages in human atherosclerosis are in fact SMC derived.
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Cholesterol accumulation in intimal smooth muscle cells can drive their conversion into pro-inflammatory macrophage-like cells.
“Intimal smooth muscle cells not only accumulate cholesterol and turn into foam cells but the cholesterol accumulation in the cell can also drive their switching into pro-inflammatory, macrophage-like cells142,143.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [142]
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- Authors
- Allahverdian, S., Chehroudi, A. C., McManus, B. M., Abraham, T., & Francis, G. A.
- Affiliations
- University of British Columbia (CA)
- From the Departments of Medicine and Pathology and Laboratory Medicine, Centre for Heart Lung Innovation, Institute for Heart + Lung Health, Providence Health Care Research Institute at St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada (S.A., A.C.C., B.M.M., G.A.F.), and Department of Research Resources, Penn State Milton S. Hershey Medical Center, Hershey, PA (T.A.).
- Venue
- Circulation
- Published
- 2014-04-15
- Volume
- 129
- Issue
- 15
- Pages
- 1551-1559
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2157280773
- Cited by
- 748
- References
- 33
- Citations by year
- 2026: 67 · 2025: 74 · 2024: 70 · 2023: 83 · 2022: 71 · 2021: 77 · 2020: 66 · 2019: 43 · 2018: 51 · 2017: 40 · 2016: 54 · 2015: 35 · 2014: 16
- FWCI
- 22.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- intimal smooth muscle cells, coronary artery disease, foam cells, cholesterol accumulation, ABCA1, macrophage-like cells, CD68, smooth muscle actin, lipid loading, plaque composition, myeloid cells, human coronary arteries
- MeSH terms
- CD68 Molecule, Actins, Cholesterol, Coronary Artery Disease, Coronary Vessels, Foam Cells, Humans, Macrophages, Muscle, Smooth, Vascular, Antigens, Differentiation, Myelomonocytic, Biomarkers, Antigens, CD, Tunica Intima, Cell Lineage, Myeloid Cells, ATP Binding Cassette Transporter 1, In Vitro Techniques
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