Abstract 5523: High Glucose Promotes Intracellular Lipid Accumulation by Impairing the Balance between CD36 and ATP-Binding Cassette Transporter G1 in Vascular Smooth Muscle Cells

Abstract

Objective: Foam cell formation is a characteristic of atherosclerotic lesions. It’s known that high glucose promotes macrophage-derived foam cell formation involved in increased influx or reduced efflux of lipids. The aim of this study is to investigate the influence of hyperglycemia on foam cell transformation of vascular smooth muscle cells (VSMCs) and possible mechanisms contributing to these effects. Methods and Results: The results showed that high glucose in cultured human aortic SMCs increased the mRNA and protein expressions of CD36, a regulator of lipid influx, and suppressed the mRNA and protein expressions of ATP binding cassette (ABC) transporters ABCG1, a regulator of cholesterol efflux to HDL, in a dose- and time-dependent manner. However, the ability of cholesterol efflux to lipid-free apoAI was not impaired. VSMCs exposed to high glucose were easily developed into lipid-loaded cells as demonstrated by oil red O staining. Meanwhile, it had a maximum 2.3-fold increase in accumulation of esterified cholesterol compared to VSMCs cultured in normal glucose. Additionally, there was no change found in either liver X receptor (LXR)α or LXRβ, suggesting that high glucose-induced down-regulation of ABCG1 was LXR-independent. Down-regulation of ABCG1 induced by high glucose was almost totally reversed by the NF-κB inhibitors BAY 11–7085, tosyl-phenylalanine chloromethyl-ketone (TPCK) and by the antioxidant N-acetyl-L-cysteine(NAC). This reversal was accompanied by reduced intracellular lipid content. Furthermore, we also demonstrated that high glucose enhanced the binding of nuclear proteins extracted from human VSMCs to the NF-κB regulatory elements. This effect was abrogated by NAC and NF-κB inhibitors. Conclusions: These results suggested that hyperglycemia-induced foam cell formation in VSMCs was related to the imbalanced lipid flux by increasing CD36 mediated modified LDL uptake and reducing ABCG1 regulated intracellular cholesterol efflux. Moreover, this effect was associated with activated NF-κB pathway signaling.