MicroRNA-27 Prevents Atherosclerosis by Suppressing Lipoprotein Lipase-Induced Lipid Accumulation and Inflammatory Response in Apolipoprotein E Knockout Mice

Abstract

Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice. To address these questions and its potential mechanisms, oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages were transfected with the miR-27 mimics/inhibitors and apoE KO mice fed high-fat diet were given a tail vein injection with miR-27 agomir/antagomir, followed by exploring the potential roles of miR-27. MiR-27 agomir significantly down-regulated LPL expression in aorta and peritoneal macrophages by western blot and real-time PCR analyses. We performed LPL activity assay in the culture media and found that miR-27 reduced LPL activity. ELISA showed that miR-27 reduced inflammatory response as analyzed in vitro and in vivo experiments. Our results showed that miR-27 had an inhibitory effect on the levels of lipid both in plasma and in peritoneal macrophages of apoE KO mice as examined by HPLC. Consistently, miR-27 suppressed the expression of scavenger receptors associated with lipid uptake in ox-LDL-treated THP-1 macrophages. In addition, transfection with LPL siRNA inhibited the miR-27 inhibitor-induced lipid accumulation and proinflammatory cytokines secretion in ox-LDL-treated THP-1 macrophages. Finally, systemic treatment revealed that miR-27 decreased aortic plaque size and lipid content in apoE KO mice. The present results provide evidence that a novel antiatherogenic role of miR-27 was closely related to reducing lipid accumulation and inflammatory response via downregulation of LPL gene expression, suggesting a potential strategy to the diagnosis and treatment of atherosclerosis.

MicroRNA-27a is a key modulator of cholesterol biosynthesis

“…Consistent with our findings, administration of miR-27a mimic in Apoe -/mice diminished lipid levels in both plasma and peritoneal macrophages, thereby alleviating atherosclerosis by targeting macrophage-derived lipoprotein lipase (Lpl) [48]. Of note, HITS-CLIP experiments revealed that miR-27a also targeted microsomal triglyceride transfer protein (Mttp), a crucial chaperone involved in lipoprotein production [49].…”

Diagnostic and theranostic microRNAs in the pathogenesis of atherosclerosis

“…It is reported that miR‐27 can inhibit the expression of inflammatory factors, such as scavenger receptors associated with lipid uptake, and decreased aortic plaque size in ApoE knockout mice. Additionality, miR‐27 overexpression can reduce lipid accumulation via the downregulation of macrophage‐derived lipoprotein lipase (LPL) expression . Interestingly, in other studies, miR‐27a can decrease the level of the LDL receptors that are important for efficient endocytosis of the LDL receptor‐LDL‐C complex .…”

MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis

“…miR-758-5p reduces macrophage oxLDL uptake by directly inhibiting expression of the scavenger receptor CD36 [76]. miR-27a/b regulates macrophage cholesterol homeostasis by targeting genes involved in cholesterol uptake (LOX-1 and CD36) and efflux (ABCA1) [77]. miR-23a-5p and miR-212 increase foam cell formation by reducing cholesterol efflux from macrophages through ABCA1 [31,78].…”

“…miR-34 increases the binding capacity of oxLDL to macrophages by facilitating bridging between lipoprotein lipase (LPL) and LOX-1 [79]. Conversely, miR-27 and miR-590 inhibit LPL expression to prevent macrophage lipid accumulation and cytokine release [77,80,81].…”