ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP
ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP
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DOI：
10.1074/jbc.ra119.011244
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发表时间：
2020-01-31
影响因子：
4.8
通讯作者：
Bernstein, Kenneth E.
中科院分区：
文献类型：
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作者：
Cao, Duo-Yao;Spivia, Weston R.;Bernstein, Kenneth E.
血管紧张素转换酶(ACE)影响血压。此外，血管紧张素转换酶在髓系细胞中的过度表达增强了它们的免疫功能。利用MS和化学分析，我们发现ACE高表达的巨噬细胞和中性粒细胞中的中间代谢产物发生了显著变化，细胞内ATP增加了1.7-3.0倍，Krebs循环中间产物包括柠檬酸、异柠檬酸、琥珀酸和苹果酸(1.4-3.9倍)。血管紧张素II AT1受体拮抗剂不能逆转血管紧张素II AT1受体拮抗剂的作用，但血管紧张素II AT1受体拮抗剂不能逆转这种作用。相比之下，来自ACE基因敲除(Null)小鼠的巨噬细胞平均只有WT小鼠的28%。ACE的过度表达不会改变细胞或线粒体的大小或数量。然而，在巨噬细胞和中性粒细胞中，电子传递链蛋白NDUFB8(复合体I)、ATP5A和ATP5β(复合体V)的表达水平显著增加，而COX1和COX2(复合体IV)在过度表达ACE的巨噬细胞中表达增加。与WT细胞相比，过量表达ACE的巨噬细胞线粒体膜电位(高24%)、ATP生成率(高29%)和最大呼吸频率(高37%)增加。随着血管紧张素转换酶表达的增加，细胞内ATP的增加支持髓系细胞超氧化物的产生和吞噬功能的增加。髓系细胞过度表达ACE提示存在一种新的途径，在该途径中髓系细胞的功能可以被增强，其关键特征是细胞内ATP的增加。
Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7-3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4-3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5 beta (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.