LPS activates ADAM9 dependent shedding of ACE from endothelial cells

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• 作者：William R. English^a ; ^{w.english@sheffield.ac.uk} ; Pierre Corvol^b ; Gillian Murphy^a
• 关键词：IL-1 ; Interleukin-1 ; TNF伪 ; Tumour Necrosis Factor alpha ; Fc ; Fc portion of IgG ; siRNA ; short interfering RNA ; PMA ; phorbol 12-myristate 13-acetate ; Mca ; (7-methoxycourmarin-4-yl)acetyl ; Dpa ; N3-(2 ; 4-dinitrophenyl)-l-2 ; 3-diaminopropionyl ; ICAM-1 ; Intracel
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：27 April, 2012
• 卷：421
• 期：1
• 页码：70-75
• 文件大小：701 K

摘要

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-魏B, TNF伪 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.