MiR-195-Sirt3 axis regulates angiotensin ii-induced hippocampal apoptosis and learning impairment in mice

Abstract

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.