MicroRNA-21 deficiency attenuated atherogenesis and decreased macrophage infiltration by targeting Dusp-8.

Abstract

BACKGROUND AND AIMS:

Atherosclerosis is a chronic inflammatory disorder mediated by macrophage activation. MicroRNA-21 (miR-21) is a key regulator in the macrophage inflammatory response. However, the functional role of miR-21 in atherogenesis is far from clear.

METHODS AND RESULTS:

Here, we report that miR-21 is significantly upregulated in mouse atherosclerotic plaques and peripheral monocytes from patients with coronary artery disease. Compared with miR-21+/+apoE-/- mice (apoE-/- mice), miR-21-/-apoE-/- (double knockout, DKO) mice showed less atherosclerotic lesions, reduced presence of macrophages, decreased smooth muscle cells(SMC) and collagen content in the aorta. We further explored the role of miR-21 in macrophage activation in vitro. Bone marrow-derived macrophages (BMDMs) from DKO mice not only exhibit impaired function of migration induced by chemokine (C-C motif) ligand 2 (CCL2) but also a weakened macrophage-endothelium interaction activated by tumor necrosis factor-α (TNF-α). However, atherogenic inflammatory cytokine secretion was not affected by miR-21 in vitro or in vivo. Additionally, miR-21 knockdown in BMDMs directly derepressed the expression of dual specificity protein phosphatase 8 (Dusp-8), a previously validated miR-21 target in cardiac fibroblasts, which negatively regulates mitogen-activated protein kinase (MAPK) signaling, particularly the p38-and c-Jun N-terminal kinase (JNK)-related signaling pathways.

CONCLUSIONS:

These data demonstrate that inhibition of miR-21 may restrict the formation of atherosclerotic plaques partly by regulating macrophage migration and adhesion, while, reduced SMCs and collagen content in plaques may lead to a less stable phenotype with the progression of atherosclerosis. Thus, the absence of miR-21 reduces atherosclerotic lesions but may not represent all benefit in atherosclerosis development.

• Authors: Lin Gao, Huasu Zeng, Tiantian Zhang, Chengyu Mao, Yue Wang, Zhihua Han, Kan Chen, Junfeng Zhang, Yuqi Fan, Jun Gu, Changqian Wang
• Journal: Atherosclerosis (Atherosclerosis) Vol. 291 Pg. 78-86 (12 2019) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 31704554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• MIRN21 microRNA, human
• MIRN21 microRNA, mouse
• MicroRNAs
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• DUSP8 protein, mouse
• Dual-Specificity Phosphatases

Topics

• Animals
• Aorta (enzymology, pathology)
• Aortic Diseases (enzymology, genetics, pathology, prevention & control)
• Atherosclerosis (enzymology, genetics, pathology, prevention & control)
• Cell Adhesion
• Chemotaxis
• Disease Models, Animal
• Dual-Specificity Phosphatases (genetics, metabolism)
• Endothelial Cells (metabolism, pathology)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Macrophage Activation
• Macrophages (enzymology, pathology)
• Male
• Mice
• Mice, Knockout, ApoE
• MicroRNAs (genetics, metabolism)
• Plaque, Atherosclerotic
• RAW 264.7 Cells
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases (metabolism)