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Published on: September 28, 2015
Protective effect of suppressor of cytokine signalling 1-based therapy in experimental abdominal aortic aneurysm
Susana Bernal1,2, Laura Lopez-Sanz1,2, Luna Jimenez-Castilla1,2
1Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), Madrid, Spain.
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.
Insights
A novel peptide mimicking suppressor of cytokine signalling-1 (SOCS1) effectively prevented abdominal aortic aneurysm (AAA) development in mice. This therapeutic approach targets inflammation and aortic dilation, offering a potential treatment for AAA.
Area of Science:
- Vascular Biology
- Immunology
- Pharmacology
Background:
- Abdominal aortic aneurysm (AAA) is a complex disease driven by inflammation, oxidative stress, and proteolytic activity.
- The JAK/STAT pathway is implicated in chronic inflammatory diseases and presents a therapeutic target.
- Suppressor of cytokine signalling-1 (SOCS1) is a negative regulator of the JAK/STAT pathway, suggesting a potential protective role.
Purpose of the Study:
- To investigate the vasculo-protective effects of SOCS1 in experimental abdominal aortic aneurysm (AAA).
- To evaluate a synthetic peptide (S1) mimicking SOCS1's inhibitory domain for AAA treatment.
Main Methods:
- A mouse model of elastase-induced AAA was used to assess the efficacy of the S1 peptide.
- Changes in aortic diameter, cellular composition, and gene expression were monitored.
- In vitro studies were conducted on cultured vascular smooth muscle cells (VSMC) and macrophages.
Main Results:
- S1 peptide significantly reduced AAA incidence, aortic dilation, and elastin degradation.
- It partially restored medial VSMC, decreased inflammatory cells, and reduced oxidative stress in AAA tissues.
- Mechanistically, S1 suppressed STAT1/3 activation, down-regulated inflammatory cytokines and metalloproteinases, and promoted anti-inflammatory M2 macrophage and contractile VSMC phenotypes.
Conclusions:
- This study demonstrates the therapeutic potential of a SOCS1-derived peptide in halting AAA progression.
- The S1 peptide effectively suppresses JAK/STAT-mediated inflammation and aortic dilation.
- S1 peptide represents a promising therapeutic strategy for treating abdominal aortic aneurysms.
