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Angiotensin-(1–9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway

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Abstract

Endothelial apoptosis caused by activation of renin-angiotensin system (RAS) plays a vital part in the occurrence and progress of hypertension. Angiotensin-(1–9) (Ang-(1–9)) is a peptide of the counter-regulatory non-classical RAS with anti-hypertensive effects in vascular endothelial cells (ECs). However, the mechanism of action remains unclear. Considering that the endothelial apoptosis was closely related to endoplasmic reticulum stress (ERS) and mitochondrial function. Herein, we aimed to elucidate the effects of Ang-(1–9) on endothelial apoptosis and the underlying molecular mechanism in angiotensin II (Ang II) induced hypertension. In human umbilical vascular endothelial cells (HUVECs), we observed Ang-(1–9) inhibited Ang II-induced ERS associated endothelial apoptosis. Mechanically, Ang-(1–9) inhibited endothelial apoptosis by blocking CNPY2/PERK mediated CaMKII/Drp1-dependent mitochondrial fission and eIF2α/CHOP signal. Consistent with above effects in HUVECs, in Ang II-induced hypertensive mice, we found administration of exogenous Ang-(1–9) attenuated endothelial apoptosis and arterial blood pressure, which were mediated by CNPY2/PERK signaling pathway. Our study indicated Ang-(1–9) inhibited Ang II-induced hypertension through CNPY2/PERK pathway. These findings may provide new insights for prevention and treatment of hypertension in future.

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Data availability

All data that support the current study findings are available from the corresponding author on reasonable request.

Change history

Abbreviations

Ang-(1–9):

Angiotensin-(1–9)

RAS:

Renin-angiotensin system

Ang II:

Angiotensin II

HUVECs:

Human umbilical vascular endothelial cells

ERS:

Endoplasmic reticulum stress

ECs:

Endothelial cells

CNPY2:

Canopy FGF signaling regulator 2

PERK:

Protein kinase R-like endoplasmic reticulum kinase

eIF2α:

Eukaryotic initiation factor 2α

ATF4:

Activating transcription factor 4

CHOP:

C/EBP-homologous protein

Drp1:

Dynamin-related protein 1

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

UPR:

Unfolded protein response

ACE 2:

Angiotensin converting enzyme type 2

ATCC:

American type culture collection

DMEM:

Dulbecco’s modified eagle medium

FBS:

Fetal bovine serum

ROS:

Reactive oxygen species

SD:

Standard deviation

SBP:

Systolic blood pressure

DBP:

Diastolic blood pressure

BAX:

BCL2-Associated X

BCL-2:

B-cell lymphoma-2

eNOS:

Endothelin nitric oxide synthase

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Acknowledgements

This work was supported by the Chinese Natural Science Foundation grants (81800171, 81900275), the Natural Science Foundation of Shanxi Province (201801D221273), the Scientific and Technological Innovation Program of Shanxi Higher Education Institution (201804026, 201804027) and Shanxi Provincial Commission of Health and Family Planning (2017053).

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  1. Chun-ling Guo, Hui-min Liu have equally contributed to this work.

Authors and Affiliations

  1. Department of Cardiology, The Second Hospital of Shanxi Medical University, 382 Wuyi Road, Taiyuan, 030001, Shanxi, China

    Chun-ling Guo, Bao Li & Zhao-yang Lu

  2. Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China

    Hui-min Liu

  3. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311100, China

    Hui-min Liu

  4. Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China

    Zhao-yang Lu

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Contributions

CLG participated in the conception and design of the work, obtained and analysed data and wrote the manuscript. HML performed the experiments and materials, and wrote the manuscript. BL designed the experiments, and wrote the manuscript. ZYL supervised the work, performed the experiments, analysed data, and wrote the manuscript.

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Correspondence to Hui-min Liu, Bao Li or Zhao-yang Lu.

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Guo, Cl., Liu, Hm., Li, B. et al. Angiotensin-(1–9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway. Apoptosis 28, 379–396 (2023). https://doi.org/10.1007/s10495-022-01793-2

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