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miR-195-Sirt3 Axis Regulates Angiotensin II-Induced Hippocampal Apoptosis and Learning Impairment in Mice

Authors Fan X, Xiao M, Zhang Q, Li N, Bu P

Received 28 June 2019

Accepted for publication 11 October 2019

Published 6 December 2019 Volume 2019:12 Pages 1099—1108

DOI https://doi.org/10.2147/PRBM.S221209

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Igor Elman


Xiaosheng Fan,1,2 Ming Xiao,1 Qinghai Zhang,1 Na Li,1 Peili Bu1

1The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic of China; 2Department of Cardiology, Laiwu People’s Hospital, Laiwu, Shandong 271100, People’s Republic of China

Correspondence: Peili Bu
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Jinan 250012, People’s Republic of China
Email bupeili@outlook.com

Objective: Apoptosis plays an essential role in cell development and aging, which is associated with a series of diseases, such as neurodegeneration. MircoRNAs exert important roles in the regulation of gene expression. As a stress-responsive deacetylase in mitochondria, sirtuin-3 (sirt3) is a key regulator for mitochondrial function and apoptosis. Also, miR-195 has been demonstrated to be involved in cell cycle and apoptosis. Therefore, this study aimed to investigate the effects of miR-195-sirt3 axis on angiotensin II (ANG II)-induced hippocampal apoptosis and behavioral influence.
Materials and methods: ANG II infusion was used to establish the hypertensive model in HT22 cells and 129S6/SvEvTac mice, respectively. TUNEL assay was used to evaluate the apoptosis level. Mitochondrial membrane potential (MMP) was measured to evaluate the mitochondrial property. Immunohistochemistry, RT-PCR, Western blotting, and luciferase reporter assay were conducted to determine the underlying molecular mechanism.
Results: The results revealed that ANG II treatment promoted apoptosis in the hippocampal cells and tissues, along with increased sirt3 and decreased miR-195 expression. Silencing sirt3 by genetic engineering or siRNA reversed ANG II-induced hippocampal apoptosis. Sirt3 was identified as a direct target gene of miR-195. Forced expression of miR-195 could play counteractive roles in hippocampal apoptosis induced by ANG II. Furthermore, the behavioral assay demonstrated that ANG II-induced hippocampal apoptosis impaired the performance in the spatial navigation task, but not in the spatial memory task.
Conclusion: The results suggested that miR-195-sirt3 axis plays an important role in the ANG II-induced hippocampal apoptosis via altering mitochondria-apoptosis proteins and mitochondria permeability and that hippocampal apoptosis is associated with impaired learning capability in hypertensive mice. This study provides insights into the molecular architecture of apoptosis-related neurodegenerative diseases.

Keywords: Sirt3, miR-195, hippocampus, apoptosis, hypertension, mitochondria, learning

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