Contribution of Intimal Smooth Muscle Cells to Cholesterol Accumulation and Macrophage-Like Cells in Human Atherosclerosis
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 AI (ABCA1) when compared to medial arterial SMCs. The relative contribution of SMCs to the total foam cell population and their expression of ABCA1 when compared to intimal monocyte-derived macrophages, however, are unknown. While 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 co-staining for cell-specific markers. Co-staining for Oil Red O and the SMC-specific marker SM α-actin of foam cell rich lesions revealed that 50±7% (avg ± SEM, 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. Co-staining 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, due in part to their relative inability to release excess cholesterol via ABCA1, when compared to myeloid-lineage cells. Our results also indicate that many cells identified as monocyte-derived macrophages in human atherosclerosis are in fact SMC-derived.
- Received July 10, 2013.
- Revision received December 13, 2013.
- Accepted January 17, 2014.