Abstract
Atherosclerosis is an inflammatory disease that leads to an aberrant accumulation of cholesterol in vessel walls forming atherosclerotic plaques. During this process, the mechanism regulating complex cellular cholesterol pools defined as the reverse cholesterol transport (RCT) is altered as well as expression and functionality of transporters involved in this process, namely ABCA1, ABCG1, and SR-BI. Macrophages, arterial endothelial and smooth muscle cells (SMCs) have been involved in the atherosclerotic plaque formation. As macrophages are widely described as the major cell type forming the foam cells by accumulating intracellular cholesterol, RCT alterations have been poorly studied at the arterial endothelial cell and SMC levels. Amongst the therapeutics tested to actively counteract cellular cholesterol accumulation, the methylated β-cyclodextrin, KLEPTOSE® CRYSMEβ, has recently shown promising effects on decreasing the atherosclerotic plaque size in atherosclerotic mouse models. Therefore we investigated in vitro the RCT process occurring in SMCs and in arterial endothelial cells (ABAE) as well as the ability of some modified β-CDs with different methylation degree to modify RCT in these cells. To this aim, cells were incubated in the presence of different methylated β-CDs, including KLEPTOSE® CRYSMEβ. Both cell types were shown to express basal levels of ABCA1 and SR-BI whereas ABCG1 was solely found in ABAE. Upon CD treatments, the percentage of membrane-extracted cholesterol correlated to the methylation degree of the CDs independently of the lipid composition of the cell membranes. Decreasing the cellular cholesterol content with CDs led to reduce the expression levels of ABCA1 and ABCG1. In addition, the cholesterol efflux to ApoA-I and HDL particles was significantly decreased suggesting that cells forming the blood vessel wall are able to counteract the CD-induced loss of cholesterol. Taken together, our observations suggest that methylated β-CDs can significantly reduce the cellular cholesterol content of cells forming atherosclerotic lesions and can subsequently modulate the expression of ABC transporters involved in RCT. The use of methylated β-CDs would represent a valuable and efficient tool to interfere with atherosclerosis pathogenesis in patients, nonetheless their mode of action still needs further investigations to be fully understood and finely controlled at the cellular level.
Highlights
Vascular dysfunction represents a key event in the pathogenesis of atherosclerosis, a chronic disease characterized by the increased deposition of cholesterol in the artery intima
In our culture conditions (DMEM), we observed that the amount of ABCG1 and SCARB1 mRNA expressed in aortic bovine arch endothelial (ABAE) were 2.33fold and 13.20-fold higher than the amount of ABCA1 mRNA, respectively
This process remains the major pathway for regulating cellular cholesterol pools and is mediated by proteins expressed by most cell types: two members of the ATP-binding cassette (ABC) transporter family, ABCA1 and ABCG1, and SR-BI (Phillips, 2014)
Summary
Vascular dysfunction represents a key event in the pathogenesis of atherosclerosis, a chronic disease characterized by the increased deposition of cholesterol in the artery intima. In the first steps of the disease, inflammatory processes lead to the recruitment of cholesterol-laden macrophages in the artery wall that form the so-called foam cells filled with numerous cholesterol ester droplets (Allahverdian and Francis, 2010). Studies in macrophages revealed that apoA-I initially interacts with ABCA1 to form a partially lipidated discoidal complex that subsequently interacts with ABCG1 in order to get additional cholesterol and to generate spherical lipoprotein particles, the high density lipoproteins (HDL) (Gelissen et al, 2006). We and others have investigated the expression pattern and functionality of SR-BI and these two ABC transporters at the macrophage level as well as their abilities to initiate and generate HDL (LinselNitschke and Tall, 2005; Wang et al, 2007; Mahmood et al, 2013; Phillips, 2014). The RCT has received little attention at the arterial endothelial cell and SMC levels (Allahverdian and Francis, 2010)
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