Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa.
Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
Int J Mol Sci. 2024 Jun 27;25(13):7055. doi: 10.3390/ijms25137055.
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.
血管紧张素转化酶（ACE）独立于其心血管分支对髓样细胞功能具有强大的调节作用。过表达 ACE 的鼠巨噬细胞模型 ACE 10/10 在治疗微生物感染和癌症方面的成功为研究人类巨噬细胞中 ACE 过表达是否具有这些益处开辟了新途径。此外，由于 ACE 抑制剂是一种广泛使用的降压药物，因此它们对表达 ACE 的免疫细胞的影响引起了人们的兴趣，目前研究还不够充分。在本研究中，我们利用质谱技术对过表达 ACE 的人 THP-1 细胞系进行了全面的蛋白质组学特征分析和评估。此外，还评估了 ACE C 结构域选择性抑制剂赖诺普利-色氨酸处理后的蛋白质组学变化和细胞摄取情况。尽管细胞内摄取有限，但抑制剂处理后 ACE 活性显著降低，并且 RNA 加工和免疫途径在治疗后均显著失调。ACE 过表达还伴随着上调的能量和 TCA 循环蛋白以及失调的细胞因子和白细胞介素信号蛋白。一种新的、功能丰富的免疫途径在 ACE 过表达和抑制剂处理中均存在，即中性粒细胞脱颗粒。人巨噬细胞中的 ACE 过表达与 ACE 10/10 鼠巨噬细胞具有相似性，为旨在了解改变的免疫功能的机制研究铺平了道路。
