Endothelial HMGB1 Is a Critical Regulator of LDL Transcytosis via an SREBP2–SR-BI Axis

• DOI: 10.1161/atvbaha.120.314557
• Publication Date: 2020-10-15T09:01:35Z
• Authors: Siavash Ghaffari; Erika Jang; Farnoosh Naderinabi; Rajiv Sanwal; Negar Khosraviani; Changsen Wang; Benjamin E. Stein...; Neil M. Goldenberg; Jiro Ikeda; Warren L. Lee
• Keywords: Transcytosis; Negative regulator

LDL (low-density lipoprotein) transcytosis across the endothelium is performed by SR-BI (scavenger receptor class B type 1) and contributes to atherosclerosis. HMGB1 (high mobility group box a structural protein in nucleus that released cells during inflammation; extracellular has been implicated advanced disease. Whether intracellular regulates through its nuclear functions unknown. Approach Results: was depleted siRNA human coronary artery endothelial cells, of measured total internal reflection fluorescence microscopy. Knockdown attenuated without affecting albumin transcytosis. Loss resulted reduction levels depletion SREBP2 (sterol regulatory element-binding 2)-a transcription factor upstream SR-BI. The effect on required SREBP2. Overexpression caused an increase unaffected inhibition or RAGE (receptor for glycation endproducts)-a cell surface HMGB1. overexpression prevented knockdown half-life SREBP2; incubation with significant localization dependent Animals lacking exhibited less acute accumulation aorta 30 minutes after injection when fed high-fat diet developed fewer fatty streaks