Research Paper Volume 14, Issue 16 pp 6809—6828

LncRNA H19 inhibits ER stress induced apoptosis and improves diabetic cardiomyopathy by regulating PI3K/AKT/mTOR axis

Sixuan Wang1, *, , Jun Duan1, *, , Jiangquan Liao2, , Yan Wang2, , Xiang Xiao2, , Lin Li2, , Yi Liu2, , Huan Gu2, , Peng Yang2, , Dongliang Fu2, , Jinhang Du2, , Xianlun Li2, , Mingjing Shao2, ,

  • 1 Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
  • 2 National Integrated Traditional and Western Medicine Center for Cardiovascular Disease, China-Japan Friendship Hospital, Beijing 100029, China
* Equal contribution and co-first authors

Received: July 5, 2021       Accepted: August 17, 2022       Published: August 30, 2022      

https://doi.org/10.18632/aging.204256
How to Cite

Copyright: © 2022 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Objective: Extensive studies have shown that ERS may be implicated in the pathogenesis of DCM. We explored the therapeutic effects of lncRNAH19 on DCM and its effect on ERS-associated cardiomyocyte apoptosis.

Methods: C57/BL-6j mice were randomly divided into 3 groups: non-DM group (controls), DM group (DCM), and lncRNAH19 overexpression group (DCM+H19 group). The effect of H19 on cardiac function was detected. The effect of H19 on cardiomyocyte apoptosis and cardiac fibrosis in DM was examined. Differentially expressed genes (DEGs) and activated pathways were examined by bioinformatics analysis. STRING database was applied to construct a PPI network using Cytoscape software. The expression of p-PERK, p-IRE1, ATF6, CHOP, cleaved caspase-3, -9, -12 and BAX proteins in cardiac tissue was used to determine the ERS-associated apoptotic indicators. We established the HG-stimulated inflammatory cell model. The expression of p-PERK and CHOP in HL-1 cells following HG was determined by immunofluorescence labeling. The effects of H19 on ERS and PI3K/AKT/mTOR pathway were also detected.

Results: H19 improved left ventricular dysfunction in DM. H19 could reduce cardiomyocytes apoptosis and improve fibrosis in vivo. H19 could reduce the expression of p-PERK, p-IRE1α, ATF6, CHOP, cleaved caspase-3, cleaved caspase-9, cleaved caspase-12, and BAX proteins in cardiac tissues. Furthermore, H19 repressed oxidative stress, ERS and apoptosis in vitro. Moreover, the effect of H19 on ERS-associated apoptosis might be rescued by LY294002 (the specific inhibitor for PI3K and AKT).

Conclusion: H19 attenuates DCM in DM and ROS, ERS-induced cardiomyocyte apoptosis, which is associated with the activation of PI3K/AKT/mTOR signaling pathway.

Abbreviations

ER: endoplasmic reticulum; DCM: Diabetic cardiomyopathy; DEGs: Differentially expressed genes; ROS: reactive oxygen species; CH: ventricular hypertrophy; UPR: unfolded protein response; ERS: endoplasmic reticulum stress; UPR: unfolded protein response; PERK: protein kinase RNA like ER kinase; ATF6: activating transcription factor-6; IRE1: inositol requiring protein 1; eIF2α: eukaryotic translation initiation factor 2α; ATF4: activates transcription factor 4; CHOP: pro-apoptotic transcription factor DNA-damage-inducible transcript 3; lncRNAs: Long non-coding RNAs; mTOR: mammalian target of rapamycin; LVESd: left ventricular end systolic diameter; LVEDd: left ventricular end diastolic diameter; LVEF: left ventricular ejection fraction; OE: overexpression; KD: knockdown; STZ: Streptozotocin; FBG: fasting blood glucose; LVEF: left ventricular ejection fraction; FS: fractional shortening; p: Phosphorylated; t: Total.