Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
J Biol Chem. 2024 Jun;300(6):107388. doi: 10.1016/j.jbc.2024.107388. Epub 2024 May 17.
As part of the classical renin-angiotensin system, the peptidase angiotensin-converting enzyme (ACE) makes angiotensin II which has myriad effects on systemic cardiovascular function, inflammation, and cellular proliferation. Less well known is that macrophages and neutrophils make ACE in response to immune activation which has marked effects on myeloid cell function independent of angiotensin II. Here, we discuss both classical (angiotensin) and nonclassical functions of ACE and highlight mice called ACE 10/10 in which genetic manipulation increases ACE expression by macrophages and makes these mice much more resistant to models of tumors, infection, atherosclerosis, and Alzheimer's disease. In another model called NeuACE mice, neutrophils make increased ACE and these mice are much more resistant to infection. In contrast, ACE inhibitors reduce neutrophil killing of bacteria in mice and humans. Increased expression of ACE induces a marked increase in macrophage oxidative metabolism, particularly mitochondrial oxidation of lipids, secondary to increased peroxisome proliferator-activated receptor α expression, and results in increased myeloid cell ATP. ACE present in sperm has a similar metabolic effect, and the lack of ACE activity in these cells reduces both sperm motility and fertilization capacity. These nonclassical effects of ACE are not due to the actions of angiotensin II but to an unknown molecule, probably a peptide, that triggers a profound change in myeloid cell metabolism and function. Purifying and characterizing this peptide could offer a new treatment for several diseases and prove potentially lucrative.
作为经典肾素-血管紧张素系统的一部分，肽酶血管紧张素转换酶（ACE）产生血管紧张素 II，对全身心血管功能、炎症和细胞增殖有多种影响。不太为人知的是，巨噬细胞和中性粒细胞在免疫激活时会产生 ACE，这对髓样细胞功能有明显影响，与血管紧张素 II 无关。在这里，我们讨论 ACE 的经典（血管紧张素）和非经典功能，并强调一种称为 ACE 10/10 的小鼠，其基因操作增加了巨噬细胞中的 ACE 表达，使这些小鼠对肿瘤、感染、动脉粥样硬化和阿尔茨海默病模型的抵抗力大大增强。在另一种称为 NeuACE 的小鼠模型中，中性粒细胞产生增加的 ACE，这些小鼠对感染的抵抗力大大增强。相比之下，ACE 抑制剂会降低小鼠和人类中性粒细胞对细菌的杀伤能力。ACE 的表达增加会诱导巨噬细胞氧化代谢的显著增加，特别是脂质的过氧化物酶体增殖物激活受体 α 表达增加导致髓样细胞 ATP 增加。精子中的 ACE 具有类似的代谢作用，而这些细胞中 ACE 活性的缺乏会降低精子的运动能力和受精能力。ACE 的这些非经典作用不是由于血管紧张素 II 的作用，而是由于一种未知的分子，可能是一种肽，触发了髓样细胞代谢和功能的深刻变化。这种肽的纯化和特性鉴定可能为几种疾病提供新的治疗方法，并具有潜在的利润。
