PDF(Pubmed)
Abstract：
Angiotensin converting enzyme (ACE) exerts strong modulation of myeloid cell function independently of its cardiovascular arm. The success of the ACE-overexpressing murine macrophage model, ACE 10/10, in treating microbial infections and cancer opens a new avenue into whether ACE overexpression in human macrophages shares these benefits. Additionally, as ACE inhibitors are a widely used antihypertensive medication, their impact on ACE expressing immune cells is of interest and currently understudied. In the present study, we utilized mass spectrometry to characterize and assess global proteomic changes in an ACE-overexpressing human THP-1 cell line. Additionally, proteomic changes and cellular uptake following treatment with an ACE C-domain selective inhibitor, lisinopril-tryptophan, were also assessed. ACE activity was significantly reduced following inhibitor treatment, despite limited uptake within the cell, and both RNA processing and immune pathways were significantly dysregulated with treatment. Also present were upregulated energy and TCA cycle proteins and dysregulated cytokine and interleukin signaling proteins with ACE overexpression. A novel, functionally enriched immune pathway that appeared both with ACE overexpression and inhibitor treatment was neutrophil degranulation. ACE overexpression within human macrophages showed similarities with ACE 10/10 murine macrophages, paving the way for mechanistic studies aimed at understanding the altered immune function.
摘要：
血管紧张素转换酶（ACE）独立于其心血管臂对髓系细胞功能具有很强的调节作用。ACE过表达的小鼠巨噬细胞模型的成功，ACE10/10在治疗微生物感染和癌症方面为ACE在人类巨噬细胞中的过表达是否共享这些益处开辟了新途径。此外,因为ACE抑制剂是一种广泛使用的抗高血压药物，它们对表达ACE的免疫细胞的影响是令人感兴趣的,目前还未得到充分研究.在本研究中,我们利用质谱来表征和评估ACE过表达的人THP-1细胞系的整体蛋白质组变化。此外,用ACEC结构域选择性抑制剂治疗后的蛋白质组变化和细胞摄取，赖诺普利-色氨酸,也进行了评估。ACE活性在抑制剂处理后显著降低，尽管细胞内的摄取有限，RNA加工和免疫途径都随着治疗而显著失调。还存在具有ACE过表达的上调的能量和TCA循环蛋白以及失调的细胞因子和白介素信号蛋白。一部小说,ACE过表达和抑制剂治疗均出现功能富集的免疫途径是中性粒细胞脱颗粒。人巨噬细胞内ACE过表达与ACE10/10鼠巨噬细胞相似，为旨在理解改变的免疫功能的机理研究铺平了道路。
