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

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.

[1]  K. Luo,et al.  Melatonin inhibits proliferation, migration, and invasion by inducing ROS-mediated apoptosis via suppression of the PI3K/Akt/mTOR signaling pathway in gallbladder cancer cells , 2021, Aging.

[2]  Lizhen Liao,et al.  NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging , 2021, Aging.

[3]  I. Massey,et al.  Role of PI3K/Akt signaling pathway in cardiac fibrosis , 2021, Molecular and Cellular Biochemistry.

[4]  Xiaoqing Chai,et al.  Sufentanil Protects the Liver from Ischemia/Reperfusion-Induced Inflammation and Apoptosis by Inhibiting ATF4-Induced TP53BP2 Expression , 2021, Inflammation.

[5]  H. Sourij,et al.  MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics , 2021, Cardiovascular Diabetology.

[6]  Weili Sun,et al.  lncRNA-MALAT1 promotes high glucose-induced H9C2 cardiomyocyte pyroptosis by downregulating miR-141-3p expression , 2021, Molecular medicine reports.

[7]  B. Patel,et al.  NRF2 in Cardiovascular Diseases: a Ray of Hope! , 2020, Journal of Cardiovascular Translational Research.

[8]  Y. Liang,et al.  Irisin improves insulin resistance by inhibiting autophagy through the PI3K/Akt pathway in H9c2 cells. , 2020, Gene.

[9]  C. Hetz,et al.  Mechanisms, regulation and functions of the unfolded protein response , 2020, Nature Reviews Molecular Cell Biology.

[10]  Xiaoyu Liu,et al.  Long non-coding RNA H19 promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by regulating microRNA-140-5p/SATB2 axis , 2020, Journal of Biosciences.

[11]  Jiang-Wen Liu,et al.  LncRNA MALAT1 regulates diabetic cardiac fibroblasts through the Hippo/YAP signaling pathway. , 2020, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[12]  Y. Osuga,et al.  Activation of endoplasmic reticulum stress mediates oxidative stress-induced apoptosis of granulosa cells in ovaries affected by endometrioma. , 2019, Molecular human reproduction.

[13]  M. Chu,et al.  Sulodexide attenuates endoplasmic reticulum stress induced by myocardial ischaemia/reperfusion by activating the PI3K/Akt pathway , 2019, Journal of cellular and molecular medicine.

[14]  Yan Wang,et al.  The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats , 2019, Drug development research.

[15]  G. Lembo,et al.  PI3Kinases in Diabetes Mellitus and Its Related Complications , 2018, International journal of molecular sciences.

[16]  C. Woo,et al.  Laminar Flow Inhibits ER Stress-Induced Endothelial Apoptosis through PI3K/Akt-Dependent Signaling Pathway , 2018, Molecules and cells.

[17]  Z. Bosnjak,et al.  Current status and strategies of long noncoding RNA research for diabetic cardiomyopathy , 2018, BMC Cardiovascular Disorders.

[18]  Siyu Li,et al.  Luteolin-mediated PI3K/AKT/Nrf2 signaling pathway ameliorates inorganic mercury-induced cardiac injury. , 2018, Ecotoxicology and environmental safety.

[19]  Xiaolong Wang,et al.  Anti‐apoptotic effect of Suxiao Jiuxin Pills against hypoxia‐induced injury through PI3K/Akt/GSK3&bgr; pathway in HL‐1 cardiomyocytes , 2018, Journal of the Chinese Medical Association : JCMA.

[20]  Shikun Liu,et al.  Palmitic acid, but not high-glucose, induced myocardial apoptosis is alleviated by N‑acetylcysteine due to attenuated mitochondrial-derived ROS accumulation-induced endoplasmic reticulum stress , 2018, Cell Death & Disease.

[21]  Xiaowu Wang,et al.  Crocin Alleviates Myocardial Ischemia/Reperfusion-Induced Endoplasmic Reticulum Stress via Regulation of miR-34a/Sirt1/Nrf2 Pathway , 2018, Shock.

[22]  Chunlei Zhang,et al.  [Effect of naringin on oxidative stress and endoplasmic reticulum stress in diabetic cardiomyopathy]. , 2018, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[23]  C. Hetz,et al.  The Unfolded Protein Response and Cell Fate Control. , 2017, Molecular cell.

[24]  Michael T. McManus,et al.  CRISPR/Cas-based screening of long non-coding RNAs (lncRNAs) in macrophages with an NF-κB reporter , 2017, The Journal of Biological Chemistry.

[25]  Xin Zhang,et al.  H3 Relaxin Protects Against Myocardial Injury in Experimental Diabetic Cardiomyopathy by Inhibiting Myocardial Apoptosis, Fibrosis and Inflammation , 2017, Cellular Physiology and Biochemistry.

[26]  Xiaofang Wang,et al.  NGF Attenuates High Glucose-Induced ER Stress, Preventing Schwann Cell Apoptosis by Activating the PI3K/Akt/GSK3β and ERK1/2 Pathways , 2017, Neurochemical Research.

[27]  T. He,et al.  lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling. , 2017, Oncotarget.

[28]  Pengyuan Yang,et al.  In-depth proteomic profiling of left ventricular tissues in human end-stage dilated cardiomyopathy , 2017, Oncotarget.

[29]  Shixue Liu,et al.  Role of microRNAs in the pathogenesis of diabetic cardiomyopathy. , 2017, Biomedical reports.

[30]  H. Yoshida,et al.  Endoplasmic Reticulum (ER) Stress and Endocrine Disorders , 2017, International journal of molecular sciences.

[31]  Li-ming Chen,et al.  Protective effects of triptolide on TLR4 mediated autoimmune and inflammatory response induced myocardial fibrosis in diabetic cardiomyopathy. , 2016, Journal of ethnopharmacology.

[32]  C. Zhuo,et al.  LncRNA H19 inhibits autophagy by epigenetically silencing of DIRAS3 in diabetic cardiomyopathy , 2016, Oncotarget.

[33]  Li Yang,et al.  LncRNA H19 functions as a competing endogenous RNA to regulate AQP3 expression by sponging miR‐874 in the intestinal barrier , 2016, FEBS letters.

[34]  Liwen Jiang,et al.  Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in plants , 2016, Protoplasma.

[35]  C. Mozzini,et al.  Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. , 2015, Free radical biology & medicine.

[36]  J. Xu,et al.  Circulating interleukin-1β promotes endoplasmic reticulum stress-induced myocytes apoptosis in diabetic cardiomyopathy via interleukin-1 receptor-associated kinase-2 , 2015, Cardiovascular Diabetology.

[37]  Xiang Wang,et al.  IDH1, a CHOP and C/EBPβ-responsive gene under ER stress, sensitizes human melanoma cells to hypoxia-induced apoptosis. , 2015, Cancer letters.

[38]  T. Lampidis,et al.  Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress. , 2015, Leukemia research.

[39]  A. Tramontano,et al.  Novel Long Noncoding RNAs (lncRNAs) in Myogenesis: a miR-31 Overlapping lncRNA Transcript Controls Myoblast Differentiation , 2014, Molecular and Cellular Biology.

[40]  H. Cai,et al.  Protein kinase RNA-like endoplasmic reticulum kinase (PERK)/calcineurin signaling is a novel pathway regulating intracellular calcium accumulation which might be involved in ventricular arrhythmias in diabetic cardiomyopathy. , 2014, Cellular signalling.

[41]  Joseph Thaddeus Beck,et al.  Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma. , 2014, Cancer treatment reviews.

[42]  Jinbao Liu,et al.  Anacardic acid induces cell apoptosis associated with induction of ATF4-dependent endoplasmic reticulum stress. , 2014, Toxicology letters.

[43]  Zhenggang Zhu,et al.  Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer , 2014, Oncotarget.

[44]  C. Porta,et al.  Targeting PI3K/Akt/mTOR Signaling in Cancer , 2014, Front. Oncol..

[45]  J. Egido,et al.  Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes , 2013, Cardiovascular Diabetology.

[46]  E. Schon,et al.  Mitochondria-associated ER membranes in Alzheimer disease , 2013, Molecular and Cellular Neuroscience.

[47]  Yasushi Hiraoka,et al.  Autophagosomes form at ER–mitochondria contact sites , 2013, Nature.

[48]  G. Wang,et al.  ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension. , 2012, The Journal of clinical investigation.

[49]  P. Vandenabeele,et al.  ER stress-induced inflammation: does it aid or impede disease progression? , 2012, Trends in molecular medicine.

[50]  F. Reis,et al.  The role of inflammation in diabetic cardiomyopathy , 2012 .

[51]  Y. Tripathi,et al.  Obesity and endoplasmic reticulum (ER) stresses , 2012, Front. Immun..

[52]  Razelle Kurzrock,et al.  PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  R. Norman,et al.  Endoplasmic reticulum (ER) stress in cumulus-oocyte complexes impairs pentraxin-3 secretion, mitochondrial membrane potential (DeltaPsi m), and embryo development. , 2012, Molecular endocrinology.

[54]  T. Uzu,et al.  SIRT1, a calorie restriction mimetic, in a new therapeutic approach for type 2 diabetes mellitus and diabetic vascular complications. , 2010, Endocrine, metabolic & immune disorders drug targets.

[55]  E. Abel,et al.  Diabetic cardiomyopathy, causes and effects , 2010, Reviews in Endocrine and Metabolic Disorders.

[56]  S. Salami,et al.  Cardioprotective effect of vitamin E: rescues of diabetes-induced cardiac malfunction, oxidative stress, and apoptosis in rat. , 2009, Journal of diabetes and its complications.

[57]  Dennis P. Nelson,et al.  Myocardial Fas Ligand Expression Increases Susceptibility to AZT-Induced Cardiomyopathy , 2007, Cardiovascular Toxicology.

[58]  Thomas H Marwick,et al.  Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. , 2004, Endocrine reviews.

[59]  P. Anversa,et al.  IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. , 2001, Diabetes.

[60]  H. Zinszner,et al.  Identification of novel stress‐induced genes downstream of chop , 1998, The EMBO journal.

[61]  V. Gomord,et al.  The C-terminal HDEL sequence is sufficient for retention of secretory proteins in the endoplasmic reticulum (ER) but promotes vacuolar targeting of proteins that escape the ER. , 1997, The Plant journal : for cell and molecular biology.

[62]  Yan-ming Sun,et al.  Recent advances in understanding the biochemical and molecular mechanism of diabetic cardiomyopathy. , 2012, Biochemical and biophysical research communications.

[63]  L. Caperuto,et al.  UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression. , 2011, American journal of physiology. Regulatory, integrative and comparative physiology.

[64]  Pierre Morel,et al.  CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.