ACE over expression in myeloid cells increases oxidative metabolism and cellular ATP
Angiotensin converting enzyme (ACE) affects blood pressure. In addition, ACE over expression in myeloid cells increases their immune function. Using mass spectrometry and chemical analysis, we identified marked changes of intermediate metabolites in ACE over expressing macrophages and neutrophils, with increased cellular ATP (1.7- to 3.0-fold) and Krebs cycle intermediates including citrate, isocitrate, succinate, and malate (1.4- to 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. Contrariwise, macrophages from ACE knockout (null) mice averaged only 28% the ATP levels found in wild type mice. ACE over expression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5β (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) in macrophages, over expressing ACE. Macrophages over expressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher) and maximal respiratory rates (37% higher) than wild type cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells over expressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.