MiR-29b Downregulation Induces Phenotypic Modulation of Vascular Smooth Muscle Cells: Implication for Intracranial Aneurysm Formation and Progression to Rupture.

Abstract

BACKGROUND/AIMS:

Our previous microarray results identified numerous microRNAs (miRNAs), including miR-29b, that were differentially expressed in the serum of intracranial aneurysm (IA) patients. The current study aimed to investigate whether miR-29b downregulation in IA could promote the phenotypic modulation of vascular smooth muscle cells (VSMCs) involved in the pathogenesis of aneurysm by activating ATG14-mediated autophagy.

METHODS:

First, the levels of miR-29b and autophagy related genes (ATGs) between IA patients and normal subjects were compared. Next, we modified the level of miR-29b via lentivirus particles in the VSMCs and examined the effects of miR-29b on proliferation, migration, and phenotypic modulation of VSMCs from a contractile phenotype to a synthetic phenotype, as well as the levels of autophagy. Finally, the binding of miR-29b to the 3'UTR of ATG14 mRNA and its effects on ATG14 expression were analysed by a luciferase reporter assay and Western blot, respectively.

RESULTS:

The level of miR-29b was decreased, and autophagy markers were increased in the IA patients compared to that of the normal subjects. Knockdown of miR-29b significantly promoted VSMCs proliferation and migration and, more importantly, induced the phenotypic modulation associated with autophagy activation, whereas miR-29b overexpression showed the opposite effects. The luciferase reporter assay demonstrated that ATG14 was a functional target gene of miR-29b. Notably, knockdown of ATG14 by siRNA apparently abrogated miR-29b inhibition-mediated phenotypic modulation.

CONCLUSION:

Downregulation of miR-29b induced VSMCs phenotypic modulation by directly activating ATG14-mediated autophagy, which is associated with the formation, growth and rupture of IAs.

• Authors: Liqian Sun, Manman Zhao, Jingbo Zhang, Ming Lv, Youxiang Li, Xinjian Yang, Aihua Liu, Zhongxue Wu
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 41 Issue 2 Pg. 510-518 ( 2017) ISSN: 1421-9778 [Electronic] Germany
• PMID: 28214880 (Publication Type: Journal Article)
• Copyright: © 2017 The Author(s) Published by S. Karger AG, Basel.

Chemical References

• ATG14 protein, human
• ATG5 protein, human
• Adaptor Proteins, Vesicular Transport
• Antagomirs
• Autophagy-Related Protein 5
• Autophagy-Related Proteins
• Beclin-1
• MicroRNAs
• RNA, Small Interfering

Topics

• Adaptor Proteins, Vesicular Transport (antagonists & inhibitors, genetics, metabolism)
• Adult
• Aged
• Aged, 80 and over
• Antagomirs (metabolism)
• Autophagy
• Autophagy-Related Protein 5 (genetics, metabolism)
• Autophagy-Related Proteins (antagonists & inhibitors, genetics, metabolism)
• Beclin-1 (genetics, metabolism)
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Disease Progression
• Female
• Humans
• Intracranial Aneurysm (diagnosis, metabolism, pathology)
• Male
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Middle Aged
• Muscle, Smooth, Vascular (cytology, metabolism)
• Phenotype
• RNA Interference
• RNA, Small Interfering (metabolism)
• Young Adult