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

Abstract

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 wellestablished 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.

Activating transcription factor 4 aggravates angiotensin II-induced cell dysfunction in human vascular aortic smooth muscle cells via transcriptionally activating fibroblast growth factor 21

“…It is estimated that the mortality rate is up to 90% upon AAA rupture [ 18 ]. Open and endovascular aneurysm repair surgery are the main therapeutic strategies for AAA; however, they are not applicable for small AAA (<rmsep 55 mm in diameter) [ 19 ]. Additionally, there is currently no effective pharmacotherapy available for AAA treatment [ 20 ].…”

Fcγ receptor activation mediates vascular inflammation and abdominal aortic aneurysm development

“…For in vivo inhibition of Syk kinase, WT mice were treated with Bay 61‐3606 (S7006, Selleckchem; 50 mg/kg body weight, intraperitoneally, 3 days per week). Dose and administration route were chosen based on the previous literature 32 . For preventive treatment, mice ( n = 7) received Bay 61‐3606 for a period of 2 weeks (from day −1 until day 14 postperfusion).…”

“…Dose and administration route were chosen based on the previous literature. 32 For preventive treatment, mice (n = 7) received Bay 61-3606 for a period of 2 weeks (from day −1 until day 14 postperfusion). For therapeutic treatment, mice (n = 5) received Bay 61-3606 for 1 week (from day 7 until day 14 postperfusion).…”

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

“…On the basis of previous mutational studies, several research groups carried out numerous studies where they demonstrated that the linear peptide spanning KIR domain (52–67) inhibits/reduces 1) the activation of STAT by cytokines Th1 and 17 in leukocytes; 2) the activation and migration of vascular cells and macrophages in vitro ( Ahmed et al, 2015 ); 3) the expression of cytokines with pro-inflammatory properties in atherosclerotic plaques ( Recio et al, 2014 ); 4) the renal inflammation, oxidative stress, and fibrosis ( Recio et al, 2017 ; Lopez-Sanz et al, 2018 ; Opazo-Ríos et al, 2020 ); 5) the chronic intraocular inflammatory disease (as uveitis) ( He et al, 2016 ; Recio et al, 2017 ; Ahmed et al, 2018 ) [very recently, in equine recurrent uveitis (ERU), that is, the only spontaneous model of human recurrent uveitis ( Larkin et al, 2020 )]; 6) the inflammation in the abdominal aortic aneurysm (AAA), to downstream target genes, and to prevent elastase formation induced by AAA ( Bernal et al, 2020 ); and 7) the severity of skin lesions, autoantibody production, and kidney disease in lupus-associated pathologies ( Sharma et al, 2021 ).…”

“…In detail, a preclinical study reported the vasculo-protective action of the SOCS1 mimetic KIR peptide in a mouse model of elastase-induced AAA ( Bernal et al, 2020 ). KIR peptide suppressed STAT1,3 activation in aorta, downregulated cytokines and metalloproteinases, altered the expression of cell differentiation markers, and reduced the incidence of AAA in aortic dilation and elastin degradation.…”