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EMBO Mol Med. 2017 Sep;9(9):1244-1262. doi: 10.15252/emmm.201607492.

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

Author information

1
Vascular Biology and Therapeutics Program, Integrative Cell Signaling and Neurobiology of Metabolism Program and the Departments of Comparative Medicine and 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.
4
Vascular Biology and Therapeutics Program, Integrative Cell Signaling and Neurobiology of Metabolism Program and the Departments of Comparative Medicine and Pathology, Yale University School of Medicine, New Haven, CT, USA carlos.fernandez@yale.edu yajaira.suarez@yale.edu.

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.

KEYWORDS:

apoptosis; atherosclerosis; macrophage polarization; miRNA

PMID:
28674080
PMCID:
PMC5582411
DOI:
10.15252/emmm.201607492
[Indexed for MEDLINE]
Free PMC Article

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