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.
Highlights
Atherosclerosis is one of the major causes leading to mortality of dysfunctional cardiovascular events in developed countries
Our group has previously demonstrated that miR-27a/b repressed the expression of endogenous Lipoprotein lipase (LPL) through binding directly to the LPL 3’UTR, and affected the metabolism of cellular cholesterol in THP-1 macrophages [28]
Our group has previously demonstrated that miR-27a/b repressed the expression of endogenous LPL through binding directly to the LPL 3’UTR in THP-1 macrophages[28]
Summary
Atherosclerosis is one of the major causes leading to mortality of dysfunctional cardiovascular events in developed countries. The atherosclerotic lesions are mostly characterized by the transformation of macrophages to foam cells through uptake of lipoprotein-derived cholesterols, which secrete various inflammatory cytokines in the arterial intima[1], suggesting a critical role for macrophages in the development of atherosclerosis[2, 3]. LPL is considered as a protector against atherosclerosis by reducing atherogenic lipoproteins in a variety of tissues, such as the heart, skeletal muscle, adipose and aorta[5,6,7]. None of these actions is thought to involve macrophage LPL, which has been suggested to have a proatherogenic role[8]. Manipulating macrophage LPL to reduce lipid accumulation and inflammatory response has been an important therapeutic goal of atherosclerosis
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