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

• Published in: Cellular physiology and biochemistry Vol. 41; no. 2; pp. 510 - 518
• Main Authors: Sun, Liqian, Zhao, Manman, Zhang, Jingbo, Lv, Ming, Li, Youxiang, Yang, Xinjian, Liu, Aihua, Wu, Zhongxue
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2017; Cell Physiol Biochem Press GmbH & Co KG
• Subjects: Adaptor Proteins, Vesicular Transport - antagonists & inhibitors; Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Adult; Age; Aged; Aged, 80 and over; Aneurysms; Antagomirs - metabolism; Apoptosis; ATG14; Autophagy; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; Autophagy-Related Proteins - antagonists & inhibitors; Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; Beclin-1 - genetics; Beclin-1 - metabolism; Cell growth; Cell Movement; Cell Proliferation; Cells, Cultured; Circulatory system; Cloning; Disease Progression; Female; Gene expression; Humans; Intracranial aneurysm; Intracranial Aneurysm - diagnosis; Intracranial Aneurysm - metabolism; Intracranial Aneurysm - pathology; Male; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; MiR-29b; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Original Paper; Pathogenesis; Phenotype; Phenotypic modulation; Physiology; Proteins; RNA Interference; RNA, Small Interfering - metabolism; Smooth muscle; Vascular smooth muscle cell; Young Adult; Beijing China; United States > US; China; MiR-29b; Vascular smooth muscle cell; ATG14; Phenotypic modulation; Autophagy; Intracranial aneurysm
• DOI: 10.1159/000456887
• ISSN: 1015-8987; 1421-9778

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.