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Inhibition of endoplasmic reticulum stress by intermedin1-53 attenuates angiotensin II–induced abdominal aortic aneurysm in ApoE KO Mice

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Abstract

Endoplasmic reticulum stress (ERS) is involved in the development of abdominal aortic aneurysm (AAA). Since bioactive peptide intermedin (IMD)1-53 protects against AAA formation, here we investigated whether IMD1–53 attenuates AAA by inhibiting ERS. AAA model was induced by angiotensin II (AngII) in ApoE KO mouse background. AngII-treated mouse aortas showed increased ERS gene transcription of caspase12, eukaryotic translation initiation factor 2a (eIf2a) and activating transcription factor 4(ATF4).The protein level of ERS marker glucose regulated protein 94(GRP94), ATF4 and C/EBP homologous protein 10(CHOP) was also up-regulated by AngII. Increased ERS levels were accompanied by severe VSMC apoptosis in human AAA aorta. In vivo administration of IMD1-53 greatly reduced AngII-induced AAA and abrogated the activation of ERS. To determine whether IMD inhibited AAA by ameliorating ERS, we used 2 non-selective ERS inhibitors phenyl butyrate (4-PBA) and taurine (TAU). Similar to IMD, PBA, and TAU significantly reduced the incidence of AAA and AAA-related pathological disorders. In vitro, AngII infusion up-regulated CHOP, caspase12 expression and led to VSMC apoptosis. IMD siRNA aggravated the CHOP, caspase12-mediated VSMC apoptosis, which was abolished by ATF4 silencing. IMD infusion promoted the phosphorylation of adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) in aortas in ApoE KO mice, and the AMPK inhibitor compound C abolished the protective effect of IMD on VSMC ERS and apoptosis induced by AngII. In conclusion, IMD may protect against AAA formation by inhibiting ERS via activating AMPK phosphorylation.

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Acknowledgements

We thank Q. Shen for immunohistochemistry. This work was supported by the Major Research Plan of the National Natural Science Foundation of China for “Regulation Mechanism of Vascular Homeostasis and Remodeling” (No. 91339203 to Y.F.Q.), the National Natural Science Foundation of China (No. 81670434 and 81270407 to Y.F.Q.), the National Natural Science Foundation of China (No. 91739301 to M.H.) and the Collaborative Innovation Center for Cardiovascular Disorders (PXM2013_014226_07_000088).

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Authors and Affiliations

  1. Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, 100083, Beijing, China

    Xian-Qiang Ni, Wei-Wei Lu, Jin-Sheng Zhang, Qing Zhu, Jin-Ling Ren & Yong-Fen Qi

  2. Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, 100083, Beijing, China

    Xian-Qiang Ni, Wei-Wei Lu, Jin-Sheng Zhang, Qing Zhu, Jin-Ling Ren, Chao-Shu Tang & Yong-Fen Qi

  3. Department of Microbiology and Parasitology, School of Basic Medical Science, Peking University, 100083, Beijing, China

    Xian-Qiang Ni, Wei-Wei Lu, Jin-Sheng Zhang, Qing Zhu, Jin-Ling Ren & Yan-Rong Yu

  4. Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

    Xiu-Ying Liu & Xiu-Jie Wang

  5. Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, 050017, Shijiazhuang, China

    Mei Han

  6. Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Science, Chinese Academy of Science, Shanghai, China

    Qing Jing

  7. Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Ministry of Education, Capital Medical University, 100029, Beijing, China

    Jie Du

Authors
  1. Xian-Qiang Ni
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  2. Wei-Wei Lu
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  3. Jin-Sheng Zhang
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  4. Qing Zhu
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  5. Jin-Ling Ren
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  6. Yan-Rong Yu
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  7. Xiu-Ying Liu
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  8. Xiu-Jie Wang
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  9. Mei Han
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  10. Qing Jing
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  11. Jie Du
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  12. Chao-Shu Tang
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  13. Yong-Fen Qi
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Corresponding author

Correspondence to Yong-Fen Qi.

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Electronic supplementary material

12020_2018_1657_MOESM1_ESM.tif

Supplemental figure 1 IMD treatment prevented the development of AAA. (A) AngII administration-induced AAA formation, and IMD Inhibited AAA development. Representative images of isolated mouse aortas after saline, AngII or AngII + IMD treatment for 28 days; arrows point to location of AAA. (B) Incidence of AAA formation after AngII and IMD administration. (C) Systolic blood pressure of mice at different times. Saline, n = 8; AngII, n = 8; AngII + IMD, n = 7. (D) Representative data from ultrasonography of surviving mice. Arrows, inner diameter of abdominal aorta. (E) Representative H&E staining. (F) Maximum abdominal aorta diameter of mouse aortas. (G) Verhoeff-van Gieson (VVG) staining, showing cell disarray and elastin fragmentation after AngII treatment but reversed by IMD administration. (H) Representative in situ zymography of matrix metalloproteinase (MMP) level in suprarenal aortas of ApoE−/− mice. Data are mean ± SD. * P < 0.05 compared with saline. # P < 0.05 compared with AngII

12020_2018_1657_MOESM2_ESM.tif

Supplemental figure 2 IMD treatment attenuated ERS via inhibiting NADPH oxidase. (A) Western blot analysis of protein levels of GRP94, p-PERK, ATF4, CHOP and cleaved-caspase12 in VSMCs. VSMCs were pretreated with IMD1-53 (10−7 mol/L) or DPI (10−5 mol/L) for 1 h, then stimulated with or without AngII (10−5 mol/L) for 4 h. β-actin was a control for protein loading. Results are representative of 3 experiments, and densitometry analysis is shown as ratio to β-actin. (B) Statistical analysis of A.(C)mRNA expression of NOX4 after siNOX4 or scramble siRNA treatment.(D) Western blot analysis and quantification of CHOP and cleaved-caspase12 expression in non-treated cells with or without siRNA treatment. β-actin was a control for protein loading. Data are mean ± SD. *P < 0.05 compared with scramble siRNA, #P < 0.05 compared with AngII. & P < 0.05 compared with AngII + siNOX4. n = 3 at least in each group. (E) Statistical analysis of D

12020_2018_1657_MOESM3_ESM.tif

Supplemental figure 3 IMD inhibits CHOP expression by ATF4 signaling in CRL1999 cells. (A) mRNA expression of ATF4 and IMD after siATF4, siIMD or scramble siRNA treatment. (B) Western blot analysis of protein levels of CHOP in CRL1999 cells. Cells were treated with or without siRNA. β-actin was a control for protein loading. (C) Western blot analysis and quantification of CHOP expression in cells with or without siRNA treatment. β-actin was a control for protein loading. *P < 0.05 compared with scramble siRNA, #P < 0.05 compared with AngII. $ P < 0.05 compared with AngII + siIMD. n = 3 at least in each group

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Ni, XQ., Lu, WW., Zhang, JS. et al. Inhibition of endoplasmic reticulum stress by intermedin1-53 attenuates angiotensin II–induced abdominal aortic aneurysm in ApoE KO Mice. Endocrine 62, 90–106 (2018). https://doi.org/10.1007/s12020-018-1657-6

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