Rosuvastatin Blocks Advanced Glycation End Products-elicited Reduction of Macrophage Cholesterol Efflux by Suppressing NADPH Oxidase Activity via Inhibition of Geranylgeranylation of Rac-1

Abstract

Adenosine triphosphate-binding membrane cassette transporter A1 (ABCA1) and ABCG1 play a crucial role in macrophage cholesterol efflux, which is a novel therapeutic target for atherosclerosis. Advanced glycation end products (AGE) and their receptor RAGE axis is involved in accelerated atherosclerosis in diabetes as well. However, the role of AGE-RAGE axis in macrophage cholesterol efflux is not fully understood. We examined here whether AGE-RAGE axis could impair cholesterol efflux from human macrophage cells, THP-1 cells by suppressing ABCA1 and ABCG1 expression. We further investigated the effects of rosuvastatin on cholesterol efflux from AGE-exposed THP-1 cells. AGE increased reactive oxygen species generation in THP-1 cells, which was completely inhibited by rosuvastatin, anti-RAGE-antibody or diphenylene iodonium chloride (DPI), an inhibitor of NADPH oxidase. The antioxidative effect of rosuvastatin on AGE-exposed THP-1 cells was significantly prevented by geranylgeranyl pyrophosphate (GGPP). AGE decreased ABCA1 and ABCG1 mRNA levels, and subsequently reduced cholesterol efflux from THP-1 cells, which was prevented by GGPP. DPI mimicked the effects of rosuvastain. The results demonstrated that rosuvastatin could inhibit the AGE-induced reduction of THP-1 macrophage cholesterol efflux by suppressing NADPH oxidase activity via inhibition of geranylgeranylation of Rac-1. Our present study provides a novel beneficial aspect of rosuvastatin in diabetes; rosuvastain may prevent the development and progression of atherosclerosis in diabetes by not only reducing serum cholesterol level, but also by improving cholesterol efflux from foam cells of the arterial wall via blocking the harmful effects of AGE on macrophages.

miR-146a-5p Antagonized AGEs- and P.g-LPS-Induced ABCA1 and ABCG1 Dysregulation in Macrophages via IRAK-1 Downregulation

“…AGEs-RAGE-mediated signal transductions are involved in NF-kB-associated mediators including p38MAPK, Rho GTPases, and Rac-1 [38][39][40]. Rebalancing ROS and antioxidant defenses can inhibit AGE-induced reduction of THP-1 macrophage cholesterol efflux via inhibition of geranylgeranylation of Rac-1 [41]. Our findings demonstrate that IRAK-1 is an intertwined modulator between AGEs-and P.g LPS-triggered dysregulation of cholesterol metabolism although AGEs, itself, cannot mediate the P.g LPS tolerance model.…”

Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes

“…Furthermore, we demonstrated that AGEs reduce adenosine triphosphate-binding membrane cassette transporter A1 (ABCA1) and ABCG1 levels in THP-1 cells and inhibit cholesterol efflux from THP-1 macrophages to apolipoprotein (apo) AI and HDL cholesterol, respectively (41). These findings suggest the involvement of the AGE-RAGE axis in impaired re-verse cholesterol transport in diabetes and accelerated foam cell formation within the atherosclerotic lesions (41,42).…”

The role of «metabolic memory» mechanisms in the development and progression of vascular complications of diabetes mellitus

“…Соответственно, AGE ингибируют выделение холестерина из макрофагов в аполипопротеин (apo) АI и липопротеиды высокой плотности. Это подтверждает роль AGE и их рецепторов при нарушении транспорта холестерина и ускорении формирования пенистых клеток внутри атеросклероти-ческих бляшек [25].…”