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

Autor: Webers M; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Yu Y; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Eyll J; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Vanderliek-Kox J; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Schun K; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Michely A; Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany., Schumertl T; Institute of Clinical Biochemistry, Hannover Medical School (MHH), Hannover, Germany., Garbers C; Institute of Clinical Biochemistry, Hannover Medical School (MHH), Hannover, Germany., Dietrich J; Institute of Pathology, University Clinics of RWTH University, Aachen, Germany., Jonigk DD; Institute of Pathology, University Clinics of RWTH University, Aachen, Germany.; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany., Krüger I; Clinic for Thoracic Surgery, Luisenhospital Aachen, Aachen, Germany., Kühnel MP; Institute of Pathology, University Clinics of RWTH University, Aachen, Germany., Martin C; Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany., Ludwig A; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Düsterhöft S; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Oct 15; Vol. 38 (19), pp. e70105.
DOI: 10.1096/fj.202402069R
Abstrakt: 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.
(© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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