Open Access

Insulin‑receptor substrate 1 protects against injury in endothelial cell models of ox‑LDL‑induced atherosclerosis by inhibiting ER stress/oxidative stress‑mediated apoptosis and activating the Akt/FoxO1 signaling pathway

  • Authors:
    • Juan Liu
    • Xu Yi
    • Yuan Tao
    • Yanjiang Wang
    • Zhiqiang Xu
  • View Affiliations

  • Published online on: September 15, 2020     https://doi.org/10.3892/ijmm.2020.4728
  • Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Oxidized low‑density lipoprotein (ox‑LDL)‑induced endothelial cell (EC) injury is a risk factor for atherosclerosis. Therefore, the present study aimed to investigate the effects of insulin‑receptor substrate 1 (IRS‑1) on injury to ox‑LDL‑exposed ECs. For this purpose, thoracic aorta tissues were isolated from rats and cultured to obtain ECs, which were then identified using immunohistochemical staining. IRS‑1 overexpression plasmid (pcDNA3.1‑IRS‑1) and IRS‑1‑small interfering RNA were synthesized and transfected into ECs pre‑exposed to ox‑LDL. MTT and TUNEL assays were performed to evaluate the cell proliferative activity and apoptosis. Intracellular reactive oxygen species (ROS) production was determined by a flow cytometry assay. Reverse transcription‑quantitative PCR was conducted to measure the peroxisome proliferator‑activated receptor gamma co‑activator 1 alpha (Ppargcla), phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose‑6‑phosphatase catalytic subunit (G6pc) gene transcription levels. Western blot analysis was then performed to determine the IRS‑1, forkhead box O1 (FoxO1), phosphorylated (p‑)FoxO1, 78‑kDa glucose‑regulated protein (GRP78), p‑eukaryotic translation initiation factor 2A (eIF2α), CHOP, Akt and p‑Akt expression levels. Immunofluorescence staining was used to evaluate p‑FoxO1 nuclear localization. The results indicated that IRS‑1 significantly enhanced the proliferative activity, whereas it inhibited the apoptosis of ECs in a model of ox‑LDL‑induced atherosclerosis compared with ECs without IRS‑1 treatment (P<0.05). IRS‑1 significantly decreased the p‑FoxO1/FoxO1 ratio compared with ECs without ox‑LDL treatment (P<0.05). IRS‑1 significantly downregulated the expression of ER stress biomarkers, including GRP78, CHOP and the p‑eIF2α/eIF2α ratio in ox‑LDL‑exposed ECs compared with ECs without ISR‑1 treatment (P<0.05). IRS‑1 significantly reduced the intracellular ROS levels in the EC models of ox‑LDL‑induced atherosclerosis compared with ECs without IRS‑1 treatment (P<0.05). Moreover, IRS‑1 promoted the phosphorylation of Akt in the EC models of ox‑LDL‑induced atherosclerosis. IRS‑1 also significantly suppressed the transcription of atherosclerosis‑associated genes in ox‑LDL‑exposed ECs compared with ECs without IRS‑1 treatment (P<0.05). Furthermore, IRS‑1 significantly increased the cytoplasmic localization of p‑FoxO1 in EC models of ox‑LDL‑induced atherosclerosis. On the whole, the findings of the present study demonstrate that IRS‑1 exerts protective effects in an EC model of ox‑LDL‑induced atherosclerosis by inhibiting ER stress/oxidative stress‑mediated apoptosis and activating the Akt/FoxO1 signaling pathway.

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Spandidos Publications style
Liu J, Yi X, Tao Y, Wang Y and Xu Z: Insulin‑receptor substrate 1 protects against injury in endothelial cell models of ox‑LDL‑induced atherosclerosis by inhibiting ER stress/oxidative stress‑mediated apoptosis and activating the Akt/FoxO1 signaling pathway. Int J Mol Med 0: 0-0, 1899
APA
Liu, J., Yi, X., Tao, Y., Wang, Y., & Xu, Z. (1899). Insulin‑receptor substrate 1 protects against injury in endothelial cell models of ox‑LDL‑induced atherosclerosis by inhibiting ER stress/oxidative stress‑mediated apoptosis and activating the Akt/FoxO1 signaling pathway. International Journal of Molecular Medicine, 0, 0-0. https://doi.org/10.3892/ijmm.2020.4728
MLA
Liu, J., Yi, X., Tao, Y., Wang, Y., Xu, Z."Insulin‑receptor substrate 1 protects against injury in endothelial cell models of ox‑LDL‑induced atherosclerosis by inhibiting ER stress/oxidative stress‑mediated apoptosis and activating the Akt/FoxO1 signaling pathway". International Journal of Molecular Medicine 0.0 (1899): 0-0.
Chicago
Liu, J., Yi, X., Tao, Y., Wang, Y., Xu, Z."Insulin‑receptor substrate 1 protects against injury in endothelial cell models of ox‑LDL‑induced atherosclerosis by inhibiting ER stress/oxidative stress‑mediated apoptosis and activating the Akt/FoxO1 signaling pathway". International Journal of Molecular Medicine 0, no. 0 (1899): 0-0. https://doi.org/10.3892/ijmm.2020.4728