ADAM10 and ADAM17 differently mediate induced pulmonary ACE release by either direct proteolysis or indirect upregulation protein synthesis

Angiotensin-converting enzyme (ACE) is expressed on lung endothelium and can promote hypertension and cardiovascular diseases. By the activity of the metalloproteinase ADAM10 ACE can be constitutively released from the cell membrane as soluble protease. The aim of this study was to further investigate the mechanisms underlying the enhanced production of soluble ACE under pathological conditions. Using in vitro models of primary human pulmonary microvascular endothelial cells (HPMECs) and primary human umbilical vein endothelial cells (HUVECs), as well as ex vivo models of human and murine precision-cut lung slices (PCLS), we examined ACE release in response to inflammatory stimuli, hypoxia, and protein kinase C (PKC) activation, in the presence or absence of ADAM10 and ADAM17 inhibitors. Our findings demonstrate that ADAM10 is the primary sheddase responsible for inducible ACE release, while ADAM17 contributes to ACE shedding via paracrine transcriptional induction through soluble mediators. Moreover, ACE release was differentially induced by lipopolysaccharide (LPS) and hypoxia in a manner dependent on the cellular or tissue context and exhibited species-specific differences in response to the tested stimuli. Importantly, inducibly released ACE displays enhanced catalytic activity attributable to its increased extracellular concentration. Collectively, our data reveal, for the first time, that inducible ACE release is directly mediated by ADAM10, indirectly facilitated by ADAM17, and is influenced by tissue-, context-, and species-dependent factors. This complex regulation of soluble ACE release in pathological settings may be involved in fine tuning vascular pathologies.