Open AccessDownregulation of microRNA-199a-5p protects cardiomyocytes in cyanotic congenital heart disease by attenuating endoplasmic reticulum stress
Author(s) -
Yang Zhou,
Weikun Jia,
Jian Zhao,
Liang Zhao,
ChenCheng Liu,
Yong Wang,
Xiao Ye
Publication year - 2017
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2017.6934
Subject(s) - atf6 , endoplasmic reticulum , downregulation and upregulation , unfolded protein response , microrna , hypoxia (environmental) , apoptosis , microbiology and biotechnology , transcription factor , activating transcription factor , medicine , biology , cancer research , chemistry , endocrinology , gene , biochemistry , organic chemistry , oxygen
Chronic hypoxia is a key pathological change in patients with cyanotic congenital heart defect (CCHD). It has been demonstrated that enhanced myocardial unfolded protein response (UPR) increases the capacity to buffer endoplasmic reticulum (ER) stress and to avoid subsequent apoptosis caused by the hypoxia that underlies CCHD. The present study was performed to determine the regulatory role of microRNAs (miRNAs) in this cytoprotective UPR process. The results revealed that miR‑199a‑5p was markedly downregulated in the cardiac tissue of patients with CCHD and in human myocardial cells cultured in hypoxic conditions. The two major UPR modulators, 78 kDa glucose‑regulated protein (GRP78) and activating transcription factor 6 (ATF6), were potential target genes of miR‑199a‑5p in CCHD myocardial specimens. In addition, the miR‑199a‑5p mimic and inhibitor were evidently able to change GRP78 and ATF6 gene expression and ER stress‑associated apoptosis in hypoxia‑treated cardiomyocytes. The interaction between miR‑199a‑5p and the ATF6 and GRP78 3'‑UTR binding sites in myocardial cells was also confirmed by luciferase assay. Thus, it is concluded that myocardial downregulation of miR‑199a‑5p favors the UPR against hypoxia‑induced ER stress in CCHD, which contributes to myocardial protection.