Protective effect of suppressor of cytokine signalling 1-based therapy in experimental abdominal aortic aneurysm
Protective effect of suppressor of cytokine signalling 1-based therapy in experimental abdominal aortic aneurysm
复制标题
基于细胞因子信号抑制因子1的疗法在实验性腹主动脉瘤中的保护作用
DOI：
10.1111/bph.15330
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发表时间：
2020-12-23
影响因子：
7.3
通讯作者：
Gomez-Guerrero, Carmen
中科院分区：
文献类型：
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作者：
Bernal, Susana;Lopez-Sanz, Laura;Gomez-Guerrero, Carmen
背景与目的腹主动脉瘤(AAA)是一种以主动脉壁慢性炎症、氧化应激和蛋白分解活性为特征的多因素疾病。针对JAK/信号转导和转录激活因子(JAK/STAT)通路是治疗慢性炎症性疾病的一种有前景的策略。我们研究了细胞因子信号转导抑制因子-1(SOCS1)在实验性AAA中的血管保护作用，SOCS1是JAK/STAT的负调节因子。实验方法通过监测腹主动脉直径、细胞组成和基因表达的变化，在已建立的弹性蛋白酶诱导的AAA小鼠模型中，评价模拟SOCS1激酶抑制域的合成细胞通透性多肽(S1)抑制STAT激活的作用。结果S1肽可阻止AAA的发生，表现为AAA发生率降低，主动脉扩张和弹性蛋白降解减少，中膜VSMC部分恢复，AAA组织炎症细胞和氧化应激减少。从机制上讲，S1通过支持抗炎M2巨噬细胞和收缩的VSMC表型，抑制主动脉STAT1/3的激活，下调细胞因子和金属蛋白酶，改变细胞分化标记物的表达。在体外，S1抑制炎症和氧化基因的表达，减少细胞迁移，逆转巨噬细胞和VSMC的表型转换。相比之下，SOCS1沉默促进了炎症反应。结论和意义这项临床前研究表明，SOCS1衍生的多肽通过抑制JAK/STAT介导的炎症和主动脉扩张，具有阻止AAA进展的治疗潜力。因此，S1肽可能是治疗AAA的一种有价值的选择。
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.