The metalloproteinase ADAM10 sheds angiotensin‐converting enzyme (ACE) from the pulmonary endothelium as a soluble, functionally active convertase

The renin‐angiotensin‐aldosterone system (RAAS) plays a critical role in the regulation of blood pressure and fluid balance, with angiotensin‐converting enzyme (ACE) being a key transmembrane enzyme that converts angiotensin I to angiotensin II. Hence, ACE activity is an important drug target in car...

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Published in:	The FASEB journal Vol. 38; no. 19; pp. e70105 - n/a
Main Authors:	Webers, Maria, Yu, Yan, Eyll, Johanna, Vanderliek‐Kox, Julia, Schun, Katharina, Michely, Anna, Schumertl, Tim, Garbers, Christoph, Dietrich, Jana, Jonigk, Danny D., Krüger, Ingo, Kühnel, Mark P., Martin, Christian, Ludwig, Andreas, Düsterhöft, Stefan
Format:	Journal Article
Language:	English
Published:	United States 15-10-2024
Subjects:	ADAM10 ADAM10 Protein - genetics ADAM10 Protein - metabolism ADAM17 ADAM17 Protein - genetics ADAM17 Protein - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals BACE2 ectodomain shedding Endothelial Cells - metabolism Endothelium, Vascular - metabolism HEK293 Cells HPMEC Humans Lung - metabolism Male Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Inbred C57BL Mice, Knockout Peptidyl-Dipeptidase A - genetics Peptidyl-Dipeptidase A - metabolism precision cut lung slices Renin-Angiotensin System - physiology renin‐angiotensin‐aldosterone system rhomboid‐like protease soluble ACE renin‐angiotensin‐aldosterone system soluble ACE BACE2 ADAM17 ectodomain shedding rhomboid‐like protease precision cut lung slices ADAM10 HPMEC
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Summary:	The renin‐angiotensin‐aldosterone system (RAAS) plays a critical role in the regulation of blood pressure and fluid balance, with angiotensin‐converting enzyme (ACE) being a key transmembrane enzyme that converts angiotensin I to angiotensin II. Hence, ACE activity is an important drug target in cardiovascular pathologies such as hypertension. Our study demonstrates that human pulmonary microvascular endothelial cells (HPMECs) are an important source of proteolytically released ACE. The proteolytic release of transmembrane proteins, a process known as ectodomain shedding, is facilitated by membrane proteases called sheddases. By knockout and inhibition studies, we identified ADAM10 (A disintegrin and metalloprotease 10) as a primary sheddase responsible for ACE release in HEK293 cells. The function of ADAM10 as primary, constitutive sheddase of ACE was confirmed in HPMECs. Moreover, we demonstrated the physiological relevance of ADAM10 for ACE shedding in ex vivo precision cut lung slices (PCLS) from human and mouse lungs. Notably, ADAM17 activity is not directly involved in ACE shedding but indirectly by regulating ACE mRNA and protein levels, leading to increased ADAM10‐mediated ACE shedding. Importantly, soluble ACE generated by shedding is enzymatically active and can thereby participate in systemic RAAS functions. Taken together, our findings highlight the critical role of ADAM10 (directly) and ADAM17 (indirectly) in ACE shedding and RAAS modulation. Angiotensin‐converting enzyme (ACE) is released from its membrane‐anchored form into the circulation by the transmembrane protease ADAM10. Soluble ACE remains enzymatically active and can modulate the renin‐angiotensin‐aldosterone system (RAAS) by converting angiotensin‐I to angiotensin‐II. In contrast, the protease ADAM17 does not directly cleave ACE but affects its expression and thus indirectly enhances ADAM10‐mediated ACE release. The intramembrane RHBDL2 can also cleave ACE in vitro but does not appear to be involved in ACE release in pulmonary microvascular endothelial cells.
Bibliography:	Maria Webers, Yan Yu, Andreas Ludwig and Stefan Düsterhöft contributed equally. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0892-6638 1530-6860 1530-6860
DOI:	10.1096/fj.202402069R