ATP-Binding Cassette Transporter A1 Expression and Apolipoprotein A-I Binding Are Impaired in Intima-Type Arterial Smooth Muscle Cells

Abstract

Background-Accumulation of excess cholesterol by intimal arterial smooth muscle cells (SMCs) contributes to the formation of foam cells in atherosclerotic lesions. The purpose of this study was to examine the expression and activity of ATP-binding cassette transporter A1 (ABCA1) in model intimal and medial arterial SMCs, in human atherosclerotic coronary artery intimal and medial layers, and in human intimal and medial SMCs. Methods and Results-Model intimal arterial SMCs showed increased cholesteryl ester accumulation, absence of apolipoprotein A-I-mediated lipid efflux, markedly diminished ABCA1 expression, and poor apoA-I binding compared with medial-layer SMCs. Total ABCA1 mRNA and SMC-specific ABCA1 protein levels were diminished in the intimal layer compared with the medial layer of atherosclerotic human coronary arteries. Increased expression of ABCA1 by liver X receptor agonist treatment or gene transfection failed to correct apolipoprotein A-I binding, lipid efflux, or high-density lipoprotein particle formation by intima-type SMCs. In addition to impaired ABCA1 expression, intima-type SMCs appear to lack a critical binding factor or factors required for the apolipoprotein A-I-ABCA1 interaction, cholesterol efflux, and high-density lipoprotein particle formation. Key Words: apolipoproteins Ⅲ atherosclerosis Ⅲ cholesterol Ⅲ lipoproteins Ⅲ muscle, smooth S mooth muscle cells (SMCs) constitute a, or the, major cell type in most stages of atherosclerosis. 1 Relatively little is known, however, about cholesterol homeostasis in arterial SMCs compared with macrophages. Like macrophages, intima-type SMCs express scavenger receptors and develop into smooth muscle foam cells containing excess cholesteryl esters. [2][3][4][5][6] Removal of cholesterol from SMCs, like other cells, is dependent on the binding of apolipoprotein A-I (apoA-I) to the cell surface and the transfer of cellular phospholipids and cholesterol to apoA-I through the actions of the ATP-binding cassette transporter A1 (ABCA1). 7,8 Previous studies have reported marked variability in apoA-I binding and apoA-I-mediated lipid efflux from arterial SMCs obtained from different species, 9,10 suggesting that the apoA-I-SMC interaction may differ depending on SMC phenotype. Recent studies have reported both increased and decreased expression of ABCA1 in atherosclerotic arteries, [11][12][13] but the relative expression of ABCA1 in intimal versus medial layers has not been described. Although ABCA1 is expressed in SMCs originating from the medial layer of normal arteries, 7 its expression in intimal SMCs has not been reported. Conclusion-ABCA1 expression is reduced in cultured model intimal and human atherosclerotic lesion Clinical Perspective on p 3231In addition to excess cholesterol accumulation, intimal SMCs are characterized by a dedifferentiated state, an increased rate of proliferation, a loss of contractility, an increased synthesis of extracellular matrix components, and a reduced expression of SMC markers, including smooth muscle ␣-actin and...

17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway

“…In the last decade, several studies have shown that in addition to macrophages, VSMCs accumulate excess intracellular cholesteryl (25,26) and give rise to a significant number of foam cells in atherosclerotic lesions (14,27). Moreover, VSMC-derived foam cells in vitro lose the expression of VSMC contractile markers, transform into macrophage-like cells (15) and express monocyte chemoattractant protein-1 (MCP-1) (16,28).…”

Up-regulation of ATP Binding Cassette Transporter A1 Expression by Very Low Density Lipoprotein Receptor and Apolipoprotein E Receptor 2

“…Upregulation of ABCA1 expression and augmentation of cholesterol efflux in macrophages could be a mechanism to offset the pro-atherogenic effect of VLDLR and apoER2 related to uptake of cholesterol-rich lipoproteins. In addition to macrophages, cells in vascular tissues, including endothelial cells and vascular smooth muscle cells, also express ABCA1 (34,35), VLDLR, and apoER2 (36,37). The ABCA1 protein expressed in these cells has been suggested to play a protective role against atherosclerosis (34,35).…”

“…In addition to macrophages, cells in vascular tissues, including endothelial cells and vascular smooth muscle cells, also express ABCA1 (34,35), VLDLR, and apoER2 (36,37). The ABCA1 protein expressed in these cells has been suggested to play a protective role against atherosclerosis (34,35). Based on the findings from this report, it is highly possible that activation of apoER2 and VLDLR in endothelial cells and vascular smooth muscle cells increases ABCA1 expression, which in turn plays an antiatherogenic role.…”

ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease

“…71 In macrophages and VSMCs derived from atherosclerotic plaques, ABCA1 expression and ApoA1-binding capacity is markedly reduced that in turn diminishes ApoA1-mediated cholesterol efflux and promotes lipid deposition. [71][72][73][74] Notably, as mentioned above, ApoA1 could be modified in atherosclerotic plaques through oxidation, nitration, and other mechanisms. This could greatly impair functional properties of intact ApoA1 and even make it dysfunctional.…”