PDF(Pubmed)
Abstract：
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.
摘要：
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）使血管紧张素II对全身心血管功能有无数的影响，炎症,和细胞增殖。鲜为人知的是,巨噬细胞和嗜中性粒细胞响应于免疫激活而产生ACE,其对与血管紧张素II无关的骨髓细胞功能具有显著影响。这里,我们讨论了ACE的经典（血管紧张素）和非经典功能，并强调了称为ACE10/10的小鼠，其中遗传操作增加了巨噬细胞的ACE表达，并使这些小鼠对肿瘤模型更具抵抗力。感染,动脉粥样硬化,和老年痴呆症。在另一个叫做NeuACE小鼠的模型中，中性粒细胞使ACE增加，这些小鼠对感染的抵抗力更强。相比之下,ACE抑制剂减少小鼠和人类中细菌的嗜中性粒细胞杀伤。ACE的表达增加诱导巨噬细胞氧化代谢的显著增加,特别是脂质的线粒体氧化，继发于PPARα表达增加，并导致骨髓细胞ATP增加。精子中存在的ACE具有类似的代谢作用，并且这些细胞中缺乏ACE活性会降低精子运动和受精能力。ACE的这些非经典作用不是由于血管紧张素II的作用，而是由于未知的分子，可能是一种肽，这引发了骨髓细胞代谢和功能的深刻变化。纯化和表征这种肽可以为几种疾病提供新的治疗方法，并证明可能有利可图。
