Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 41, Issue 6, Pages E354-E368Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.120.316063
Keywords
atherosclerosis; cholesterol; foam cells; macrophages; myocytes; smooth muscle
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Funding
- CIHR (Canadian Institutes of Health Research) [156137, 148883]
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The study found that the inherently low level of LAL in SMCs compared with macrophages is associated with reduced capacity to catabolize atherogenic lipoproteins, which is a mechanism for SMC foam cell formation in atherosclerosis.
OBJECTIVE: We previously reported smooth muscle cells (SMCs) represent >= 50% of foam cells in human coronary and approximate to 70% in apoE (apolipoprotein E)-deficient mouse aortic atheromas and exhibit reduced expression of the cholesterol exporter ABCA1 (ATP-binding cassette transporter A1). A major stimulus for ABCA1 expression is flux of cholesterol out of lysosomes, generated by hydrolysis of lipoprotein cholesteryl esters by LAL (lysosomal acid lipase). In this study, we investigated the potential role lysosomal dysfunction might play in foam cell formation by arterial SMCs. APPROACH AND RESULTS: Human monocyte-derived macrophages (macrophages) and arterial SMCs were treated with aggregated LDL (low-density lipoprotein) to increase intracellular cholesterol and investigated for lysosomal and postlysosomal cholesterol metabolism defects. Human and mouse atheromas were analyzed for LAL expression. Unlike macrophages, aggregated LDL uptake failed to upregulate ABCA1 expression, downregulate new cholesterol synthesis, or to significantly increase 27-hydroxycholesterol levels in SMCs. Confocal microscopy revealed retention of neutral lipids within lysosomal compartments in SMCs, while macrophages showed most lipids as cytosolic droplets. LIPA (lipase A) mRNA levels and LAL protein were markedly reduced in SMCs. Treatment of SMCs with medium containing LAL resulted in significantly reduced lysosomal lipid accumulation and increased cholesterol efflux to apoA-I (apolipoprotein AI). Human and mouse atheromas exhibited low LAL/Lipa expression in intimal SMCs when compared with intimal macrophages. CONCLUSIONS: These findings indicate the inherently low level of LAL in SMCs compared with macrophages is associated with reduced capacity to catabolize atherogenic lipoproteins and is a mechanism for SMC foam cell formation in atherosclerosis.
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