Abstract
Elevated plasma low density lipoprotein (LDL) is an established risk factor for cardiovascular disease. In addition to being able to cross the endothelial barrier to become accumulated in subendothelial space and thereby initiate atherosclerosis, LDL may exert a direct effect on vascular endothelial cells through activation of LDL receptor and its downstream signaling. Whether LDL can modulate the signaling for autophagy in endothelial cells is not clear. The present study firstly demonstrated that LDL can suppress endothelial autophagy through activation of the PI3K/Akt/mTOR signaling pathway and can promote glucose uptake by translocating glucose transporter 1 (GLUT1) from cytoplasm to cell membrane, actions similar to those of insulin. A co-immunoprecipitation assay found that LDL receptor (LDLR) and insulin receptor (IR) formed a complex in HUVECs. Knock down of the insulin receptor by small interfering RNA blocked the suppression of autophagy by LDL, as well as the signaling pathway involved. We conclude that LDL may mimic the action of insulin in endothelial cells, which might partly explain the increased incidence of diabetes in patients receiving some LDL-lowering therapy.
Highlights
Low density lipoprotein is intricately involved in the atherogenic process leading to cardiovascular disease[1]
Additional to being accumulated in the subendothelial space and initiating atherosclerosis by changing endothelial permeability[8], low density lipoprotein (LDL) may exert a direct effect on vascular endothelial cells through activation of LDL receptors and downstream signaling events, e.g. cell proliferation[9], apoptosis[10,11] or permeability[8,12], etc
LY294002 reduced the phosphorylation of mTOR (Ser2448) and Akt (Ser473) in the presence or absence of LDL and mitigated the change in LC3-II and p62 expression due to LDL treatment (Fig. 2C), demonstrating that LY294002 attenuated the suppression of autophagy caused by LDL. These results suggest that the suppression of autophagy caused by LDL in HUVECs was significantly attenuated by inhibition of the PI3K/AKT/mTOR signaling pathway, suggesting that this is the mechanism by which inhibition of autophagy is caused by LDL in HUVECs
Summary
Low density lipoprotein is intricately involved in the atherogenic process leading to cardiovascular disease[1]. Autophagy regulates cell survival or death, it is involved in the modulation of a number of important cellular functions such as permeability[14,15] and angiogenesis[16], etc. Impaired autophagy in endothelial cells has been reported to play a significant role in cardiovascular diseases[17]. We identified the effects of LDL on autophagy in endothelial cells and the intracellular signaling pathway involved, further comparing the effects of LDL with insulin, the most important molecule associated with the regulation of blood glucose homeostasis
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