An Agomir of miR-144-3p Accelerates Plaque Formation through Impairing Reverse Cholesterol Transport and Promoting Pro-Inflammatory Cytokine Production

Abstract

AimsATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins, which then form nascent HDL, a key step in the mechanism of reverse cholesterol transport (RCT). While a series of microRNAs (miRNAs) have been identified as potent post-transcriptional regulators of lipid metabolism, their effects on ABCA1 function and associated mechanisms remain unclear.Methods and ResultsABCA1 was identified as a potential target of miR-144-3p, based on the results of bioinformatic analysis and the luciferase reporter assay, and downregulated after transfection of cells with miR-144-3p mimics, as observed with real-time PCR and western blot. Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE−/− mice. Clinical studies additionally revealed a positive correlation of circulating miR-144-3p with serum CK, CK-MB, LDH and AST in subjects with AMI.ConclusionsOur findings clearly indicate that miR-144-3p is essential for the regulation of cholesterol homeostasis and inflammatory reactions, supporting its utility as a potential therapeutic target of atherosclerosis and a promising diagnostic biomarker of AMI.

MiR-144 Inhibits Proliferation and Induces Apoptosis and Autophagy in Lung Cancer Cells by Targeting TIGAR

“…miRNAs function via base pairing with complementary sequences within mRNA molecules [20,21,22,23], cutting off the mRNA molecule on target genes, or inhibiting translation of target genes. Some research has indicated that miR-144 is downregulated in many cancers [24,25,26,27,28,29,30,31]. These previous findings coincide with our results, which identified that miR-144 is significantly downregulated in human lung cancer.…”

Circulating microRNAs predict future fatal myocardial infarction in healthy individuals – The HUNT study

“…These findings indicate that miR-144-3p may be a potential therapeutic target of atherosclerosis. Furthermore, clinical studies have shown a positive correlation between circulating miR-144-3p and serum creatine kinase, lactate dehydrogenase and aspartate aminotransferase in subjects with AMI [46].…”

“…A common feature for several of the differentially expressed miRs (miR-26a-5p, miR-106a-5p, miR-144-3p and miR-148b-3p) are their mutual target, the ATP-binding cassette, sub-family A, member 1 (ABCA1) [46,[61][62][63][64]. ABCA1 is the major regulator of cellular cholesterol and fundamental to the initiation and progression of atherosclerosis.…”

“…In our study, we found increased circulating levels of miR-144-3p in the participants that later suffered from fatal AMI. In apoE −/− mice increased levels of miR-144-3p in macrophage-derived foam cells inhibited cholesterol efflux, decreased circulating levels of HDL and impaired reverse cholesterol transport in vivo, thereby accelerating atherosclerosis [46,48]. Increasing the levels of miR-144-3p, by mimics and agomirs, has been shown to enhance the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro.…”

MicroRNAs in Atherosclerosis

“…MiR-33 deletion has been shown to result in worsening of obesity and liver steatosis in rodent models [99]. MiR-144-3p has also been shown to target ABCA1, agomirs of which inhibited foam cell cholesterol efflux in vitro and led to an acceleration of atherosclerosis in ApoE-/- mice in vivo [100]. Furthermore, circulating miR-144-3p levels correlated with serum creatine kinase, lactate dehydrogenase and aspartate aminotransferase in patients with acute MI.…”