LPS activates ADAM9 dependent shedding of ACE from endothelial cells

English, William R ORCID: https://orcid.org/0000-0003-3024-2441, Corvol, Pierre and Murphy, Gillian (2012) LPS activates ADAM9 dependent shedding of ACE from endothelial cells. Biochemical and Biophysical Research Communications, 421 (1). pp. 70-75. ISSN 0006-291X

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Abstract

Angiotensin-I converting enzyme (ACE) is a zinc dependent peptidase with a major role in regulating vasoactive peptide metabolism. ACE, a transmembrane protein, undergoes proteolysis, or shedding, by an as yet unidentified proteinase to release a catalytically active soluble form of the enzyme. Physiologically, soluble ACE in plasma is derived primarily from endothelial cells. We demonstrate that ACE shedding from confluent endothelial cells is increased in response to bacterial lipopolysaccharide, but not phorbol esters. Characterisation of lipopolysaccharide stimulated shedding showed that there is a lag phase before soluble ACE can be detected which is sensitive to inhibitors of translation, NF-κB, TNFα and TNFR-I/II. The shedding phase is less sensitive to these inhibitors, but is ablated by BB-94, a Matrix Metalloproteinase (MMP)/A Disintegrin and Metalloproteinase (ADAM) inhibitor. Tissue Inhibitor of Metalloproteinase (TIMP) profiling suggested a requirement for ADAM9 in lipopolysaccharide induced ACE shedding, which was confirmed by depletion with siRNA. Transient transfection of ADAM9 and ACE cDNAs into HEK293 cells demonstrated that ADAM9 requires both membrane anchorage and its catalytic domain to shed ACE.

Item Type:	Article
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	15 Dec 2022 11:31
Last Modified:	19 Oct 2023 03:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/90206
DOI:	10.1016/j.bbrc.2012.03.113

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