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Protective effect of suppressor of cytokine signalling 1-based therapy in experimental abdominal aortic aneurysm.

Authors
  • Bernal, Susana1, 2
  • Lopez-Sanz, Laura1, 2
  • Jimenez-Castilla, Luna1, 2
  • Prieto, Ignacio1, 2
  • Melgar, Ana1
  • La Manna, Sara1
  • Martin-Ventura, Jose Luis1, 3
  • Blanco-Colio, Luis Miguel1, 3
  • Egido, Jesus1, 2
  • Gomez-Guerrero, Carmen1, 2
  • 1 Renal, Vascular and Diabetes Research Lab. IIS-Fundacion Jimenez Diaz (IIS-FJD). Autonoma University of Madrid (UAM), Madrid, Spain. , (Spain)
  • 2 Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. , (Spain)
  • 3 Spanish Biomedical Research Centre in Cardiovascular Diseases (CIBERCV), Madrid, Spain. , (Spain)
Type
Published Article
Journal
British Journal of Pharmacology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Oct 21, 2020
Identifiers
DOI: 10.1111/bph.15293
PMID: 33085771
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Targeting Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a promising strategy for chronic inflammatory diseases. We investigated the vasculoprotective role of suppressor of cytokine signalling-1 (SOCS1), the negative JAK/STAT regulator, in experimental AAA. A synthetic, cell permeable peptide (S1) mimic of SOCS1 kinase inhibitory domain to suppress STAT activation was evaluated in the well-established mouse model of elastase-induced AAA by monitoring changes in aortic diameter, cellular composition, and gene expression in abdominal aorta. S1 function was further evaluated in cultured vascular smooth muscle cells (VSMC) and macrophages exposed to elastase or elastin-derived peptides. S1 peptide prevented AAA development, evidenced by reduced incidence of AAA, aortic dilation and elastin degradation, partial restoration of medial VSMC, and decreased inflammatory cells and oxidative stress in AAA tissue. Mechanistically, S1 suppressed STAT1/3 activation in aorta, downregulated cytokines and metalloproteinases, and altered the expression of cell differentiation markers by favouring anti-inflammatory M2 macrophage and contractile VSMC phenotypes. In vitro, S1 suppressed the expression of inflammatory and oxidative genes, reduced cell migration, and reversed the phenotypic switch of macrophages and VSMC. By contrast, SOCS1 silencing promoted inflammatory response. This preclinical study demonstrates the therapeutic potential of SOCS1-derived peptide to halt AAA progression by suppressing JAK/STAT-mediated inflammation and aortic dilation. S1 peptide may therefore be a valuable option for the treatment of AAA. This article is protected by copyright. All rights reserved.

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