Cellular cholesterol homeostasis in vascular endothelial cells

Abstract

Atherosclerosis is a disease of blood vessel walls that is thought to be initiated as a reaction of insults to the endothelium. The complex sequence of cellular events that begins with focal inflammation leads to the accumulation of leukocytes in the subendothelial layer and unrestricted uptake of oxidized lipoproteins by macrophages and smooth muscle cells, leading to foam cell formation. Vascular endothelial cells do not undergo the foam cell transformation and do not accumulate cholesterol in atherosclerotic plaques to the same extent as macrophages or smooth muscle cells. However, vascular endothelial cells express receptors for oxidized lipoproteins, and have the biochemical pathways for sterol synthesis and receptor-mediated endocytosis of lipoproteins. Data from the authors' laboratory show that high density lipoproteins but not lipid-free apolipoprotein A-I promote cellular cholesterol efflux in human umbilical vascular endothelial cells and human aortic endothelial cells. Gene expression microarrays were used to examine the differential expression of genes after cholesterol loading. While sterol regulatory element-binding protein-sensitive genes were downregulated, the authors identified a novel transporter, the ATP-binding cassette G1 (ABCG1) to be highly expressed in response to both cellular cholesterol loading and stimulation with the liver X receptor agonist 22-hydroxycholesterol. The ABCA1 gene and protein, the major modulator of cellular cholesterol efflux in macrophages and in peripheral and hepatic tissues, are only weakly expressed in human umbilical vascular endothelial cells and human aortic endothelial cells. These data suggest that endothelial cells maintain cholesterol homeostasis by downregulating cholesterol synthesis and low density lipoprotein receptors and by a cellular cholesterol efflux mechanism onto low-affinity but high-capacity high density lipoproteins. The role of ABC-type transporters, including ABCG1, requires further examination.

Figure 1)

Electron microphotograph of an atherosclerotic plaque in a nonhuman primate fed an atherogenic diet (2). From reference with permission

Figure 2)

Cellular cholesterol efflux in human umbilical vein endothelial cells (HUVEC) and fibroblasts. Cells were loaded with ³H cholesterol (20 μg/mL) and incubated in the presence of apoliprotein (apo) AI (50 μg/mL) or high density lipoprotein (HDL₃) (50 μg/mL), as previously described (11,20). BSA Bovine serum albumin; TD Tangier disease

Figure 3)

ATP-binding cassette transporter A1 (ABCA1) and ABCG1 protein expression in human umbilical vein endothelial cells (HUVEC) and fibroblasts. Cells were stimulated with cholesterol (chol) (20 μg/mL) or 22(R)-hydroxycholesterol (22OH) (2.5 μg/mL), as previously described (20) (ligand for the liver-specific receptor liver X receptor that upregulates the ABCA1 and ABCG1 transporters). HSP70 Heat shock protein 70