MicroRNA-590 Inhibits Lipoprotein Lipase Expression and Prevents Atherosclerosis in apoE Knockout Mice.

Ping He ,Feng Yao,Liang Li,Chao-Ke Tang,Xi-Long Zheng,Duo Gong,Chong Huang,Wei Xie,Dan Liu,Gang Lan,Yuan Li,Min Zhang,Yun-Cheng Lv,Hui Zhong ,Haipeng Cheng ,Zhaoxia Li ,Zongbao Wang ,Yanhong Tan ,Xin Ouyang ,Wang Yin

doi:10.1371/journal.pone.0138788

Abstract

Recent studies have suggested that miR-590 may play critical roles in cardiovascular disease. This study was designed to determine the effects of miR-590 on lipoprotein lipase (LPL) expression and development of atherosclerosis in apolipoprotein E knockout (apoE−/−) mice and explore the potential mechanisms. En face analysis of the whole aorta revealed that miR-590 significantly decreased aortic atherosclerotic plaque size and lipid content in apoE−/− mice. Double immunofluorescence staining in cross-sections of the proximal aorta showed that miR-590 agomir reduced CD68 and LPL expression in macrophages in atherosclerotic lesions. MiR-590 agomir down-regulated LPL mRNA and protein expression as analyzed by RT-qPCR and western blotting analyses, respectively. Consistently, miR-590 decreased the expression of CD36 and scavenger receptor A1 (SRA1) mRNA and protein. High-performance liquid chromatography (HPLC)analysis confirmed that treatment with miR-590 agomir reduced lipid levels either in plasma orinabdominal cavity macrophages of apoE−/− mice. ELISA analysis showed that miR-590 agomir decreased plasma levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukin-1β (IL-1β)and interleukin-6 (IL-6). In contrast, treatment with miR-590 antagomir prevented or reversed these effects. Taken together, these results reveal a novel mechanism of miR-590 effects, and may provide new insights into the development of strategies for attenuating lipid accumulation and pro-inflammatory cytokine secretion.

Highlights

Cardiovascular disease caused by atherosclerosis is the number one cause of death in Western countries and threatens to become the major cause of morbidity and mortality worldwide[1]
It is known that atherosclerosis is characterized by the progressive pathological changes, and the rupture of an advanced atherosclerotic lesion may cause the death of patients with atherosclerotic coronary artery disease[22]
We used miR-590 gain-of-function and miR-590 loss-of-function approaches by taking advantage of miR-590 agomir and miR-590 antagomir to examine whether miR-590 overexpression and inhibition influenced the formation of atherosclerotic plaque in apoE−/− mice fed high fat diet

Summary

Introduction

Cardiovascular disease caused by atherosclerosis is the number one cause of death in Western countries and threatens to become the major cause of morbidity and mortality worldwide[1]. Nowadays the incidence of cardiovascular disease is going up rapidly in epidemic proportions in developing countries[2].Atherosclerotic lesions are characterized by the accumulation of abundant lipids and macrophage-derived foam cells. Macrophage LPL stimulates the secretion of inflammatory cytokines and promotes the formation of atherosclerotic lesions. It has been demonstrated that expression of LPL by the macrophage promoted foam cell formation and development of atherosclerosis [7].Kawashima revealed that suppression of LPL expression was correlated with up-regulation of ABCA1 mRNA levels, and resulted in an apparent increase in subsequent ABCA1-dependent cholesterol efflux [8]. Macrophage LPL plays an important role in the development of atherosclerosis because of its promoting effects onpro-inflammatory cytokine expression and lipid composition

Methods

Results

Conclusion