Mechanisms of LDL Transcytosis during Basal and Inflammatory States

Coronary artery disease is a leading cause of mortality worldwide. There is abundant literature concerning the late stages of its underlying cause, atherosclerosis, which is initiated by deposition of low-density lipoproteins (LDL) under the endothelium of arteries to form plaques. This process also involves the inflammatory system at most stages, from recruitment of leukocytes to expression of pro-inflammatory cytokines, such that it is now recognized that atherosclerosis is a chronic inflammatory disease. However, the route of LDL passage across the endothelium has historically been overlooked. It was previously believed that LDL crossed by paracellular transport via gaps between endothelial cells. Conversely, newer research supports the notion that LDL crosses through individual endothelial cells by an active process termed transcytosis, and that LDL transcytosis contributes to atherogenesis and is stimulated by various pro-atherogenic factors. The process initiates with uptake of LDL via receptors scavenger receptor BI (SR-BI) and activin receptor-like kinase 1 (ALK1) in caveolae. The canonical LDL receptor (LDLR) is not required. Nevertheless, the mechanisms of LDL transcytosis under basal and inflammatory states are still largely unknown. Here, I show that inflammation by IL-1β increased LDL transcytosis in vitro and in vivo through LDLR, the GTPase Rab27a, and the Rab27a effector, JFC1. This has implications for atherosclerosis since LDLR is not required for basal LDL transcytosis and Rab27a is a novel regulator of LDL transcytosis. I also show that novel mediators of LDL transcytosis can be identified by performing mass spectrometry on isolated membrane microdomains containing caveolin-1, the scaffolding protein in caveolae. Using this method, myosin heavy chain 9 (MYH9) was identified. MYH9 was found to mediate exocytosis of LDL during transcytosis in vitro. In vivo, endothelial MYH9 was involved in accumulation of LDL within the aortic endothelium of mice and also contributed to atherogenesis without affecting plasma lipid levels. MYH9 also has implications in human disease – public human RNA datasets showed greater MYH9 RNA expression in atherosclerotic tissues compared to controls. Furthermore, inflammation (TNFα)-stimulated transcytosis of LDL required MYH9. In summary, we have characterized novel pathways for basal and inflammation-induced LDL transcytosis. These findings have important implications for atherogenesis.

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