Chalcone Derivatives Enhance ATP-Binding Cassette Transporters A1 in Human THP-1 Macrophages

Abstract

Atherosclerosis is a process of imbalanced lipid metabolism in the vascular walls. The underlying pathology mainly involves the deposition of oxidized lipids in the endothelium and the accumulation of cholesterol in macrophages. Macrophages export excessive cholesterol (cholesterol efflux) through ATP-binding cassette transporter A1 (ABCA1) to counter the progression of atherosclerosis. We synthesized novel chalcone derivatives and assessed their effects and the underlying mechanisms on ABCA1 expression in macrophages. Human THP-1 macrophages were treated with synthetic chalcone derivatives for 24 h. In Western blot and flow cytometry analyses, a chalcone derivative, (E)-1-(3,4-diisopropoxyphenyl)-3-(4-isopropoxy-3-methoxyphenyl)prop- 2-en-1-one (1m), was observed to significantly enhance ABCA1 protein expression in THP-1 cells (10 µM, 24 h). Levels of mRNA of ABCA1 and liver X receptor alpha (LXRα) were quantified using a real-time quantitative polymerase chain reaction technique and were found to be significantly increased after treatment with the novel chalcone derivative 1m. Several microRNAs, including miR155, miR758, miR10b, miR145, miR33, and miR106b, which functionally inhibit ABCA1 expression were suppressed after treatment with 1m. Collectively, 1m increases ABCA1 expression in human THP-1 macrophages. The mechanisms involve the activation of the LXRα-ABCA1 pathway and suppression of certain microRNAs that regulate ABCA1 expression.

Candidate SNP Markers of Atherogenesis Significantly Shifting the Affinity of TATA-Binding Protein for Human Gene Promoters Show Stabilizing Natural Selection as a Sum of Neutral Drift Accelerating Atherogenesis and Directional Natural Selection Slowing It

“…Human gene MIR10B contains one unannotated SNP, rs1388274194, able to elevate the miR-10b level (Figure 2f), and another one, rs564940769, which can reduce it (Table 9). Next, a keyword search of PubMed [38] pointed to a biochemical research article [173] about an miR-10b deficit as an atheroprotector. That is why we recommend two candidate SNP markers (rs1388274194 and rs564940769) of speeding up and slowing down atherogenesis, respectively (Table 9).…”

A chalcone derivative, 1m‐6, exhibits atheroprotective effects by increasing cholesterol efflux and reducing inflammation‐induced endothelial dysfunction

“…We previously revealed that the chalcone derivative, 1m, enhances ABCA1 expression in THP‐1 macrophages (Teng et al, 2018). To develop a more potent and multifunctional molecule than 1m, we synthesized six chalcone derivatives: 1m ‐ 1 to 1m‐6 (Figures S1A and 1a).…”

“…Kelch-like ECH-associated protein 1 is a repressor protein that binds to Nrf2 and promotes its degradation. The conformation change of kelch-like ECH-associated protein 1 results in nuclear translocation of Nrf2 and subsequent target gene expression (Kansanen, Kuosmanen, Leinonen, & Levonen, 2013;Taguchi, Motohashi, & Yamamoto, 2011). Accordingly, the effects of 1m-6 on kelch-like ECH-associated protein 1 inhibition require further investigation in future studies.…”

“…The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay was applied to assess cell viability as previously described (Teng et al, 2018). Briefly, THP‐1 cells (4 × 10 4 cells) were seeded in 96‐well plates in the culture medium.…”

“…We previously demonstrated that a novel chalcone derivative, 1m, up‐regulates ABCA1 expression in THP‐1 macrophages (Teng et al, 2018). To develop a multifaceted compound for atherosclerotic cardiovascular disease treatment, we identified another novel chalcone derivative, 1m‐6, which promotes cholesterol efflux by up‐regulating ABCA1 expression in macrophages and attenuates TNF‐α‐induced endothelial dysfunction.…”