Research Paper Volume 13, Issue 4 pp 5164—5184

Inhibition of Notch1-mediated inflammation by intermedin protects against abdominal aortic aneurysm via PI3K/Akt signaling pathway

Xian-Qiang Ni1,2,3, *, , Ya-Rong Zhang1,2,3, *, , Li-Xin Jia4, , Wei-Wei Lu1,2,3, , Qing Zhu1,2,3, , Jin-Ling Ren1,2,3, , Yao Chen1,2,3, , Lin-Shuang Zhang1,2,3, , Xin Liu1,2,3, , Yan-Rong Yu3, , Mo-Zhi Jia3, , Zhong-Ping Ning5, , Jie Du4, , Chao-Shu Tang2,3, , Yong-Fen Qi1,2,3, ,

  • 1 Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China
  • 2 Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing 100083, China
  • 3 Department of Pathogen Biology, School of Basic Medical Science, Peking University, Beijing 100083, China
  • 4 Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, Beijing 100029, China
  • 5 Shanghai University of Medicine and Health Sciences, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
* Equal contribution

Received: April 3, 2020       Accepted: October 27, 2020       Published: February 1, 2021      

https://doi.org/10.18632/aging.202436
How to Cite

Copyright: © 2021 Ni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The Notch1-mediated inflammatory response participates in the development of abdominal aortic aneurysm (AAA). The vascular endogenous bioactive peptide intermedin (IMD) plays an important role in maintaining vascular homeostasis. However, whether IMD inhibits AAA by inhibiting Notch1-mediated inflammation is unclear. In this study, we found Notch intracellular domain (NICD) and hes1 expression were higher in AAA patients’ aortas than in healthy controls. In angiotensin II (AngII)-induced AAA mouse model, IMD treatment significantly reduced AAA incidence and maximal aortic diameter. IMD inhibited AngII-enlarged aortas and -degraded elastic lamina, reduced NICD, hes1 and inflammatory factors expression, decreased infiltration of CD68 positive macrophages and the NOD-like receptor family pyrin domain containing 3 protein level. IMD inhibited lipopolysaccharide-induced macrophage migration in vitro and regulated macrophage polarization. Moreover, IMD overexpression significantly reduced CaCl2-induced AAA incidence and down-regulated NICD and hes1 expression. However, IMD deficiency showed opposite results. Mechanically, IMD treatment significantly decreased cleavage enzyme-a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) level. Pre-incubation with IMD17-47 (IMD receptors blocking peptide) and the phosphatidylinositol 3-kinase/protein kinase b (PI3K/Akt) inhibitor LY294002 reversed ADAM10 level. In conclusion, exogenous and endogenous IMD could inhibit the development of AAA by inhibiting Notch1 signaling-mediated inflammation via reducing ADAM10 through IMD receptor and PI3K/Akt pathway.

Abbreviations

AAA: abdominal aortic aneurysm; AngII: angiotensin II; IMD: intermedin; CaCl2: calcium chloride; VSMC: vascular smooth muscle cell; MMP: matrix metalloproteinase; DLL4: delta-like canonical Notch ligand 4; ADAM: a disintegrin and metalloproteinase; NICD: Notch intracellular domain; CGRP: calcitonin gene-related peptide; CRLR/RAMPs: calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes; DAPT: N-[N-(3,5-difluorophenacetyl)-Lalany]-S-phenylglycine t-butyl ester; LPS: lipopolysaccharide; IFN-γ: interferon; IL-4: interleukin-4; MCP-1: monocyte chemotactic protein-1; TNF-α: tumor necrosis factor-α; NF-κB: nuclear factor κB; PI3K/Akt: phosphatidyl inositol 3-kinase/proteinkinase b; cAMP/PKA: cyclic adenosine monophosphate/proteinkinase A; iNOS: inducible nitric oxide synthase; NLRP3: NOD-like receptor family pyrin domain containing 3; Arg1: arginase 1; ASC: apoptosis-associated speck-like protein containing CARD; PBA: 4-phenylbutyric acid; BMDMs: bone marrow-derived macrophages; HE: hematoxylin and eosin; VVG: Verhoeff-van Gieson; PBS: phosphate buffered saline.