Macrophage deficiency of miR‐21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis

Alberto Canfrán‐Duque,Marta Fernández‐Fuertes,Lidia Daimiel,Elisa Araldi,Rebeca Busto,Xinbo Zhang,Carlos Fernández‐Hernando,Noemi Rotllan,Cristina Ramírez‐Hidalgo,Yajaira Suárez

doi:10.15252/emmm.201607492

Abstract

Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR‐21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR‐21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR‐21 expression influences foam cell formation, sensitivity to ER‐stress‐induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR‐21 in macrophages increases the expression of the miR‐21 target gene, MKK3, promoting the induction of p38‐CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post‐translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR‐21 in atherogenesis.

Highlights

MicroRNAs are an established class of well-conserved, short non-coding RNAs, known to play major roles in most, if not all, biological processes by influencing the stability and translation of mRNAs (Ambros, 2004; Bartel, 2004; Filipowicz et al, 2008)
Results miR-21 is highly expressed in monocytes/macrophages, and its absence in hematopoietic cells enhances the progression of atherosclerosis
We initially determined the expression of miRNAs expressed in primary bone marrow-derived macrophages (BMDMs) by RNA sequencing. miR-21 was highly expressed in BMDMs, accounting for 42% of total raw reads (Fig 1A)

Summary

Introduction

MicroRNAs (miRNAs) are an established class of well-conserved, short non-coding RNAs, known to play major roles in most, if not all, biological processes by influencing the stability and translation of mRNAs (Ambros, 2004; Bartel, 2004; Filipowicz et al, 2008). Several reports have demonstrated a key role for miR-21 in resolving inflammation and negatively regulating pro-inflammatory responses, including many of the same stimuli that trigger miR-21 induction itself (Sheedy et al, 2010; Sheedy, 2015) These include lipopolysaccharide (LPS) and tumor necrosis factor-a (TNF-a), which initiate the inflammatory circuit and prime the cells of the immune system for action. Increased miR-21 expression is linked with conditions involving altered immune response including psoriasis, chronic bacterial inflammation, and asthma (Lu et al, 2009; Sheedy et al, 2010; Guinea-Viniegra et al, 2014) These findings suggest that miR-21 dysregulation may contribute to the pathogenesis of these diseases by promoting an anti-inflammatory, immunosuppressive environment. MiR-21 expression has been associated with a “M2-like phenotype”, Pathology, Yale University School of Medicine, New Haven, CT, USA 2 Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal de Investigación Sanitaria (IRyCIS), Madrid, Spain 3 Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Madrid, Spain

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Results

Conclusion