Dipeptidyl peptidase-4 is increased in the abdominal aortic aneurysm vessel wall and is associated with aneurysm disease processes

BackgroundAbdominal aortic aneurysm (AAA) is a potentially life-threatening disease, and until today there is no other treatment available than surgical intervention. Dipeptidyl peptidase-4 (DPP4)-inhibitors, used clinically to treat type 2 diabetes, have in murine models been shown to attenuate aneurysm formation and decrease aortic wall matrix degradation, inflammation and apoptosis. Our aim was to investigate if DPP4 is present, active and differentially expressed in human AAA.Methods and resultsDPP4 gene expression was elevated in both media and adventitia of AAA tissue compared with control tissue, as measured by microarrays and qPCR, with consistent findings in external data. The plasma activity of DPP4 was however lower in male patients with AAA compared with age- and gender-matched controls, independently of comorbidity or medication. Immunohistochemical double staining revealed co-localization of DPP4 with cells positive for CD68, CD4 and -8, CD20, and SMA. Gene set enrichment analysis demonstrated that expression of DPP4 in AAA tissue correlated with expression of biological processes related to B- and T-cells, extracellular matrix turnover, peptidase activity, oxidative stress and angiogenesis whereas it correlated negatively with muscle-/actin-related processes.ConclusionDPP4 is upregulated in both media and adventitia of human AAA and correlates with aneurysm pathophysiological processes. These results support previous murine mechanistic studies and implicate DPP4 as a target in AAA disease.

背景：腹主动脉瘤（Abdominal aortic aneurysm, AAA）是一种潜在致命性疾病，截至目前除手术干预外暂无其他有效治疗方案。二肽基肽酶-4（Dipeptidyl peptidase-4, DPP4）抑制剂临床常用于治疗2型糖尿病，现有小鼠模型研究证实其可减轻动脉瘤形成，抑制主动脉壁基质降解、炎症反应与细胞凋亡。本研究旨在探究DPP4在人类腹主动脉瘤组织中是否存在、是否具有活性，以及是否存在差异表达。

方法与结果：通过微阵列（microarrays）与实时定量聚合酶链反应（qPCR）检测发现，与对照组织相比，腹主动脉瘤组织的中膜与外膜中DPP4基因表达水平均显著升高，该结果在外部数据集中得到了一致验证。然而，与年龄、性别匹配的对照人群相比，男性腹主动脉瘤患者的血浆DPP4活性更低，且该差异不受合并症或用药情况的影响。免疫组织化学双染色结果显示，DPP4与CD68、CD4及CD8、CD20、平滑肌肌动蛋白（Smooth Muscle Actin, SMA）阳性细胞共定位。基因集富集分析表明，腹主动脉瘤组织中DPP4的表达与B细胞、T细胞相关生物学过程、细胞外基质周转、肽酶活性、氧化应激及血管生成呈正相关，而与肌肉/肌动蛋白相关生物学过程呈负相关。

结论：人类腹主动脉瘤组织的中膜与外膜中DPP4均表达上调，且与动脉瘤的病理生理过程密切相关。本研究结果佐证了此前的小鼠机制研究，并提示DPP4可作为腹主动脉瘤疾病的潜在治疗靶点。