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

Background and Purpose Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by chronic inflammation, oxidative stress and proteolytic activity in the aortic wall. Targeting JAK/signal transducer and activator of transcription (JAK/STAT) pathway is a promising strategy for chroni...

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Bibliographic Details
Published in:British journal of pharmacology 2021-02, Vol.178 (3), p.564-581
Main Authors: Bernal, Susana, Lopez‐Sanz, Laura, Jimenez‐Castilla, Luna, Prieto, Ignacio, Melgar, Ana, La Manna, Sara, Martin‐Ventura, Jose Luis, Blanco‐Colio, Luis Miguel, Egido, Jesus, Gomez‐Guerrero, Carmen
Format: Article
Language:English
Subjects:
Abdomen
abdominal aortic aneurysm
Aneurysms
Animals
Aorta
Aorta, Abdominal
Aortic Aneurysm, Abdominal - chemically induced
Aortic Aneurysm, Abdominal - drug therapy
Aortic Aneurysm, Abdominal - prevention & control
Aortic aneurysms
Cell adhesion & migration
Cell differentiation
Coronary vessels
Cytokines
Disease Models, Animal
Elastase
Elastin
Gene expression
Inflammation
Inflammatory diseases
JAK/STAT signalling
Kinases
Leukocyte migration
Macrophages
Mice
Mice, Inbred C57BL
Muscle contraction
Myocytes, Smooth Muscle
Oxidative stress
Peptides
peptidomimetic
Phenotypes
Proteolysis
Signal Transduction
Smooth muscle
SOCS-1 protein
SOCS1
Stat1 protein
Suppressor of Cytokine Signaling 1 Protein - therapeutic use
Transcription
vascular biology
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Summary:Background and Purpose Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by chronic inflammation, oxidative stress and proteolytic activity in the aortic wall. Targeting JAK/signal transducer and activator of transcription (JAK/STAT) pathway is a promising strategy for chronic inflammatory diseases. We investigated the vasculo‐protective role of suppressor of cytokine signalling‐1 (SOCS1), the negative JAK/STAT regulator, in experimental AAA. Experimental Approach 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. Key Results 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, down‐regulated cytokines, 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. Conclusion and Implications 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.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.15330