Aspirin regulates expression and function of scavenger receptor‐BI in macrophages: studies in primary human macrophages and in mice

Abstract

Scavenger receptor class B type I (SR-BI) has been shown to be expressed in human atherosclerotic plaque macrophages, where it is believed to reduce atherosclerosis by promoting cholesterol efflux. In this study we investigated the influence of aspirin and other NSAIDs on SR-BI expression and function in cultured human macrophages as well as in different mouse strains. Incubation of human macrophages with 0.5 mmol/l aspirin resulted in increased SR-BI protein expression and increased uptake of HDL-associated [3H]cholesteryl oleate without changes of SR-BI mRNA levels. In contrast, using 5 mmol/l of aspirin, SR-BI expression and function were significantly decreased. Sodium salicylate exerted similar effects on SR-BI expression, whereas no effects were observed using known COX1/2 inhibitors ibuprofen and naproxen, respectively. In in vivo studies low-dose aspirin treatment (6 mg/kg.day) induced SR-BI expression in wild-type and PPAR-alpha knockout mice, respectively, whereas the opposite effect was observed upon high-dose aspirin treatment (60 mg/kg.day) in these animals. We could show that COX-independent effects of aspirin were able to enhance expression of SR-BI in macrophages in a post-transcriptional, PPAR-alpha independent way, suggesting a novel pharmacologic effect of aspirin.

Aspirin Increases Apolipoprotein-A-I-Mediated Cholesterol Efflux via Enhancing Expression of ATP-Binding Cassette Transporter A1

“…However, at aspirin concentrations of 1.0 mmol/l or higher, the opposite effect was observed. These results agree with data published by Tancevski et al [5] showing that there is an increased SR-BI protein expression in primary human macrophages on treatment with 0.5 mmol/l aspirin, and a decreased SR-BI protein expression when the concentration of aspirin exceeds 1.0 mmol/l.…”

“…SR-BI is one of the molecules mediating cholesterol efflux in macrophages; whether aspirin is able to induce the expression of other mediators promoting reverse cholesterol transport is not known [5] . The ATP-binding cassette transporter (ABC)A1 has previously been identified as a pivotal gene in the regulation of both cellular cholesterol homeostasis and plasma high-density lipoprotein (HDL) cholesterol levels.…”

Molecular Biology of Atherosclerosis

“…PDZK1 is highly expressed in liver, intestine, and kidney, and in humans, in adrenal, ovary, and testis as well (1523). It is not expressed in macrophages (1752). In hepatocytes, PDZK1 deficiency leads to 95% reduction in SR-B1 expression, but no effect on macrophage SR-B1 expression and little effect in endothelial cells was seen.…”

The thyromimetic T-0681 protects from atherosclerosis

“…Anti-rabbit 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase was from Upstate (Millipore, Billerica, MA). Human SR-BI was detected using anti-CLA-1 from BD (BD Biosciences, Franklin Lakes, NJ) as described (19). The chemoluminescent reaction was performed using Super Signal West Dura Reagent (Pierce, Rockford, IL), and blots were visualized by Fluor-S-Imager using Quantity One V4.1 software (Bio-Rad, Hercules, CA).…”

“…At a confluency of 70%, HepG2 cells were incubated with 50 mg/ml of acetylated LDL (AcLDL) for 24 h and subsequently treated with indicated amounts of T-0681 in serum-free medium for another 24 h. Cellular protein extraction and Western blot analysis were performed as described (19).…”