Inhibition of mTOR down-regulates scavenger receptor,class B,type I (SR-BI) expression,reduces endothelial cell migration and impairs nitric oxide production |
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Authors: | Stefanie Fruhwürth Sigurd Krieger Katharina Winter Margit Rosner Mario Mikula Thomas Weichhart Robert Bittman Markus Hengstschläger Herbert Stangl |
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Institution: | 1. Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria;2. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria;3. Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria;4. Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY, USA |
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Abstract: | The mammalian target of rapamycin (mTOR) inhibiting drug rapamycin (Sirolimus) has severe side effects in patients including hyperlipidemia, an established risk factor for atherosclerosis. Recently, it was shown that rapamycin decreases hepatic LDL receptor (LDL-R) expression, which likely contributes to hypercholesterolemia. Scavenger receptor, class B, type I (SR-BI) is the major HDL receptor and consequently regulating HDL-cholesterol levels and the athero-protective effects of HDL. By using the mTOR inhibitor rapamycin, we show that SR-BI is down-regulated in human umbilical vein endothelial cells (HUVECs). This reduction of SR-BI protein as well as mRNA levels by about 50% did not alter HDL particle uptake or HDL-derived lipid transfer. However, rapamycin reduced HDL-induced activation of eNOS and stimulation of endothelial cell migration. The effects on cell migration could be counteracted by SR-BI overexpression, indicating that decreased SR-BI expression is in part responsible for the rapamycin-induced effects. We demonstrate that inhibition of mTOR leads to endothelial cell dysfunction and decreased SR-BI expression, which may contribute to atherogenesis during rapamycin treatment. |
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Keywords: | ABCG1 ATP binding cassette transporter G1 BP-C Bodipy-cholesterol BP-CE Bodipy-cholesteryl oleate CETP cholesteryl ester transfer protein DAF-2 DA 4 5-diaminofluorescein diacetate DiI 1 1&prime -dioctadecyl-3 3 3&prime 3&prime -tetramethylindocarbocyanine perchlorate FAS fatty acid synthase HCAECs human coronary artery endothelial cells HUVECs human umbilical vein endothelial cells LDL-R LDL-receptor LXR liver X receptor mTOR mammalian target of rapamycin mTORC1 mTOR complex 1 mTORC2 mTOR complex 2 PPARγ peroxisome proliferator-activated receptor gamma S6 ribosomal protein S6 S6K1 S6 kinase 1 S1P sphingosine-1-phosphate SR-BI scavenger receptor class B type I SREBP sterol regulatory element binding protein RCT reverse cholesterol transport TSC2 tuberous sclerosis 2 protein |
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