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.
Highlights
Atherosclerosis is the leading cause of cardiovascular diseases including myocardial infarction, stroke, unstable angina, and sudden cardiac death worldwide [1]
Treatment of 1m concentration-dependently enhanced LXRα protein expression at 6 h, but it did not alter the expression of PPARγ (Figure 3C). These results suggest that LXRα is involved in 1m-induced ATP-binding cassette transporter A1 (ABCA1) expression in THP-1 macrophages
We demonstrated that treatment with 1m in THP-1 macrophages significantly increase LXRα but not PPARγ expression, indicating that LXRα instead of PPARγ is the main target of this pharmacological action
Summary
Atherosclerosis is the leading cause of cardiovascular diseases including myocardial infarction, stroke, unstable angina, and sudden cardiac death worldwide [1]. Molecules 2018, 23, 1620 has been considered a chronic proinflammatory consequence of excess deposition of oxidized low-density lipoprotein (oxLDL) in arterial walls [2,3]. A process by which cholesterol is transferred from peripheral tissues and cells to the liver for biliary secretion, contributes to protection from atherosclerosis. Excess oxLDL is considered to be counterbalanced by cholesterol efflux mediated mainly by reverse cholesterol transporters (RCT) [7]. ATP-binding cassette transporter A1 (ABCA1), a major RCT, exports excess cholesterol from cells to apolipoprotein A-I and mediates the synthesis of high-density lipoprotein (HDL) cholesterol. Human epidemiology studies have shown an inverse relationship between HDL cholesterol and cardiovascular events [8,9,10]. Cholesterol efflux capacity is inversely associated with the incidence of cardiovascular events demonstrated in a population-based cohort [11]
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