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

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.

Mitochondria‐associated endoplasmic reticulum membranes tethering protein VAPB‐PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy

“…However, it is unclear whether impaired MAMs after CIRI affect oxidative stress and autophagy through PI3K/AKT/mTOR. The modulation of the PI3K/AKT/mTOR pathway may be influenced by factors such as Ca 2+ transfer, ER stress, and mitochondrial function, all of which are closely associated with MAMs, highlighting the potential role of MAMs 55–57 . Therefore, we speculated that post‐CIRI MAMs might mediate oxidative stress and autophagy through PI3K/AKT/mTOR and verified it.…”

“…The modulation of the PI3K/AKT/mTOR pathway may be influenced by factors such as Ca 2+ transfer, ER stress, and mitochondrial function, all of which are closely associated with MAMs, highlighting the potential role of MAMs. 55 , 56 , 57 Therefore, we speculated that post‐CIRI MAMs might mediate oxidative stress and autophagy through PI3K/AKT/mTOR and verified it. The results show that the PI3K activator can partially reverse the aggravation of injury in CIRI mice induced by VAPB or PTPIP51 reduction, which is manifested by attenuating oxidative stress and autophagy, reducing cerebral infarction volume and improving neurological function.…”

“…The modulation of the PI3K/AKT/ mTOR pathway may be influenced by factors such as Ca 2+ transfer, ER stress, and mitochondrial function, all of which are closely associated with MAMs, highlighting the potential role of MAMs. [55][56][57] Therefore, we speculated that post-CIRI MAMs might mediate oxi-…”

Esaxerenone Protects against Diabetic Cardiomyopathy via Inhibition of the Chemokine and PI3K-Akt Signaling Pathway

“…These mutations have been found to be associated with myocardial fibrosis and cardiac dysfunction [27]. Additionally, studies have shown that excessive activation of PIK3CA and PIK3CB may lead to increased myocardial cell proliferation and inflammation, exacerbating the pathological process of DCM [28]. Playing a pivotal role in governing the progression of the cell cycle, particularly in cellular proliferation and division, CDK4 emerges as a vital protein [29].…”

Biomarkers of heart failure: advances in omics studies

“…55 Supplementary research has shown that lncRNA H19 through inhibition of PI3K/AKT/mTOR signaling pathways mediating effector molecules, such as p-PERK, p-IRE1 alpha, ATF6, CHOP and caspase cascade, inhibits the apoptosis pathway, thereby improving diabetic cardiomyopathy. 56 Hobuß et al used the H19 knockout mouse model to verify the regulatory role of lncRNA H19 in post-infarction myocardium, revealing its role in cellular mechanisms, including myocardial cell apoptosis and inflammatory response, leading to adverse cardiac remodeling. 57 In terms of modulating cardiac fibrosis, lncRNAs like LINC01013 have made strides, being recognized as potential novel regulators influencing the onset and progression of myocardial fibrosis.…”