Abstract
In endothelial cells, high density lipoprotein cholesterol (HDL) binding to scavenger receptor class B, type I (SR-BI) promotes the production of the antiatherogenic signaling molecule nitric oxide (NO) and also endothelial repair. To study how SR-BI in endothelium impacts atherosclerosis, we bred newly-created floxed SR-BI mice, vascular endothelial cadherin promoter-driven Cre recombinase transgenic (VECad-Cre), and apoE -/- mice to generate apoE -/- with normal endothelial SR-BI expression (SR-BI ECIN ;apoE -/- ) or selective deletion of SR-BI from endothelium (SR-BI ECOUT ;apoE -/- ). At weaning all mice were placed on an atherogenic diet (20% fat, 1.25% cholesterol), and plasma lipid profiles and atherosclerosis were evaluated 8 weeks later. Endothelial deletion of SR-BI did not alter the plasma lipid profile. Surprisingly, male SR-BI ECOUT ;apoE -/- mice displayed 63% less atherosclerosis in the en face aorta than male SR-BI ECIN ;apoE -/- mice, aortic root lesions were comparably affected, and similar findings were obtained in females. Recognizing that SR-BI binds both HDL and low density lipoprotein cholesterol (LDL), to then discern how endothelial SR-BI promotes atherosclerosis we determined using Di-I-labeled oxidized LDL (oxLDL) if SR-BI influences oxLDL uptake by endothelial cells. Such uptake is the first step in the endothelial transcytosis that delivers LDL to the artery wall to initiate atherogenesis. OxLDL uptake by primary human aortic endothelial cells was blunted by 87% by SR-BI blocking antibody, and it was also decreased by SR-BI deletion via siRNA, and by the chemical inhibitor of SR-BI BLT-1. Furthermore, SR-BI blocking antibody and BLT-1 caused marked declines in endothelial oxLDL transcytosis. Moreover, 4 hours following IV administration, oxLDL uptake in aorta was decreased by 84% in SR-BI ECOUT ;apoE -/- versus SR-BI ECIN ;apoE -/- mice. These collective findings indicate that endothelial SR-BI plays an important role in atherogenesis, and that it likely does so by mediating LDL uptake into the artery wall. They further suggest that there are mechanisms that govern LDL transport across endothelium that may be targeted to provide novel means to combat atherosclerosis.
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