巨噬细胞HO-1调控iNOS在小鼠腹主动脉瘤中的作用及机制

Abdominal aorta aneurysm (AAA) is an inflmmatory disorder. Macrophage as a key inflammatory cell plays a pivotal role in the development of AAA. HO-1 is the rate-limiting enzyme of degradation of heme with effect of inflammatory regulation. Macrophage-derived HO-1 was reported to promote inflammation, however, the role of macrophage-derived HO-1 in AAA remains unclear. Our preliminary study showed that both in human and mouse AAA model HO-1 was increased in macrophage. The studies have reported that iNOS knockout or inhibitor inhibited the expression of iNOS and the serum level of NO, which was associated with alleviating the extent of aortic dilation, indicating a positive correlation between the expression of iNOS and the extent of AAA. We further found silence of HO-1 in macrophage can reduce the level of iNOS and NO. Hence, we hypothesized that HO-1 affects the progression of AAA via regulating iNOS. Therefore, we will employ macrophage conditional HO-1 knockout mouse AAA models, cell co-culture systems and gene interference technology to verify whether macrophage-derived HO-1 promotes the progression of AAA via iNOS. Our study is expected to reveal new mechanisms of pathogenesis of AAA and to provide evidence for macrophage-derived HO-1 as a new therapy target for clinics.

腹主动脉瘤（AAA）是一种炎症性疾病，巨噬细胞作为重要的炎症细胞在AAA中起重要作用。血红素氧合酶-1（HO-1）是催化降解血红素的限速酶，调控炎症反应。最新研究发现巨噬细胞HO-1促进炎症，但其在AAA的作用尚未见报道。我们前期研究发现AAA人体标本和小鼠AAA模型瘤壁中巨噬细胞HO-1表达增多。有研究证实iNOS基因敲除或特异性抑制剂使iNOS表达及血浆NO浓度减少，抑制AAA的扩张，提示iNOS的表达和AAA形成呈正相关。我们进一步研究发现下调巨噬细胞HO-1表达显著降低iNOS的mRNA及蛋白表达。因此我们推测巨噬细胞HO-1通过调控iNOS信号通路影响AAA形成。本项目拟采用已构建的巨噬细胞条件性HO-1基因敲除小鼠AAA模型，细胞共培养和基因干扰等技术，阐明巨噬细胞HO-1在AAA中的作用及调控iNOS信号通路的机制，本研究有助于阐明AAA发病机制和寻找潜在药物作用靶点。

腹主动脉瘤（AAA）是一种炎症性疾病，巨噬细胞作为重要的炎症细胞在AAA中起重要作用。血红素氧合酶-1（HO-1）是催化降解血红素的限速酶，调控炎症反应。最新研究发现巨噬细胞HO-1促进炎症，但其在AAA的作用尚未见报道。我们前期研究发现AAA人体标本和小鼠AAA模型瘤壁中巨噬细胞HO-1表达增多。本项目采用巨噬细胞条件性HO-1基因敲除小鼠构建小鼠AAA模型，应用细胞共培养和基因干扰等技术证实：巨噬细胞条件性HO-1 基因敲除抑制小鼠AAA的形成。巨噬细胞HO-1敲除小鼠AAA瘤体局部iNOS及过氧亚硝酸盐表达下降。细胞实验证实HO-1表达下调通过调控巨噬细胞iNOS-NO的表达减少平滑肌细胞凋亡。本研究有助于阐明AAA发病机制和寻找潜在药物作用靶点。

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