Low LAL (Lysosomal Acid Lipase) Expression by Smooth Muscle Cells Relative to Macrophages as a Mechanism for Arterial Foam Cell Formation

Abstract

Objective: We previously reported smooth muscle cells (SMCs) represent ≥50% of foam cells in human coronary and ≈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 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.

Autophagy Is Differentially Regulated in Leukocyte and Nonleukocyte Foam Cells During Atherosclerosis

“…3,[43][44][45] In contrast, agLDL loading of VSMCs results in lysosomal trapping of agLDL-associated cholesterol, with these cells remaining devoid of established LDs and failing to upregulate ABCA1. 12,42 several studies have shown VSMC conversion to foam cells following incubation with mβ-CD-cholesterol complexes, with mβ-CD-cholesterol-derived cholesterol bypassing initial lysosome lipoprotein processing and allowing for their conversion to foam cells. 14,15,26 VSMC conversion to foam cells is accompanied by loss of expression of VSMC markers and acquisition of expression of macrophage markers.…”

Macrophages in Atherosclerosis, First or Second Row Players?

“…A major study from the Francis group revealed that in human coronary artery sections, at least 50% of total intimal foam cells were derived from VSMCs and that about 40% of CD68+ cells were of VSMC rather than myeloid origin [ 103 ]. They also showed that the gene expressions of the cholesterol exporter protein ATP-Binding Cassette A1 (ABCA1) and lysosomal acid lipase (LAL), a cytosolic enzyme which hydrolyzes cholesteryl esters (the main form of cholesterol storage) to free cholesterol, were significantly reduced in VSMC-foam cells but not in macrophages-foam cells, suggesting that VSMCs may contain a much larger burden of lipids than macrophages, as they are unable to release excess lipid via ABCA1 and LAL [ 103 , 104 ]. In line with this observation, a study found that TNF ligand-related molecule 1A (TL1A), a vascular endothelial growth inhibitor reducing neovascularization, was able to inhibit the development of atherosclerosis by regulating VSMC (but not macrophage) foam cell formation by activating ABCA1, ABCG1 and cholesterol efflux by a liver X Receptor (LXR)-dependent signaling pathway [ 105 ].…”

“…However, VSMC-derived foam cells lack the cellular machinery to properly efflux accumulated cholesterol. For instance VSMCs have reduced expression of ABCA1 [ 215 , 290 ], and low expression of lysosomal acid lipase (LAL) [ 104 ] compared with macrophages. As a result, increasing ABCA1 and LAL expression in foam cells (especially in VSMCs) seems to be a promising therapeutic strategy to reduce atherosclerotic plaque burden.…”

Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis

“…Interestingly, the level of the soluble LDL receptor-related protein 1 in the circulating blood is increased in patients with coronary artery disease ( 92 , 93 ). When compared with cultured human macrophages, cultured human SMCs express relatively low levels of LAL ( 94 ). Accordingly, in SMC foam cells, the ingested neutral lipids tend to accumulate within lysosomes, while in macrophages they appear as cytosolic droplets.…”