Document Detail

Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator.
MedLine Citation:
PMID:  15307819     Owner:  NLM     Status:  MEDLINE    
MMPs (matrix metalloproteinases) play a major role in the pathogenesis of hypertension by altering the extracellular matrix during cardiovascular remodelling. In the present study we show that MMP-2, but not MMP-9, cleaves the vasodilator peptide AM (adrenomedullin). Addition of the AM-binding protein, complement factor H, prevents this cleavage, providing a hitherto unknown mechanism of action for this binding protein. We identified the signature cleavage fragments and found some of them in human urine, suggesting that MMP-2 processing of AM may occur in vivo. Synthetic AM fragments regulated blood pressure in rats. The larger peptides are vasodilators, as is intact AM, whereas intermediate fragments did not affect blood pressure. In contrast, AM(11-22) elicited vasoconstriction. Studies of AM receptor activation in Rat2 cells confirm that the larger AM cleavage peptides activated this receptor, whereas AM(11-22) did not. The present study defines a new mechanism through which MMP-2 may regulate blood pressure by simultaneously eliminating a vasodilator and generating a vasoconstrictor.
Alfredo Martínez; Hae-Ryong Oh; Edward J Unsworth; Claudia Bregonzio; Juan M Saavedra; William G Stetler-Stevenson; Frank Cuttitta
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Biochemical journal     Volume:  383     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-10-25     Completed Date:  2005-05-11     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  413-8     Citation Subset:  IM    
Cell and Cancer Biology Branch and Vascular Biology Faculty, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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MeSH Terms
Blood Pressure
Cell Line
Chemical Fractionation / methods
Chromatography, High Pressure Liquid / methods
Cyclic AMP / metabolism
Fibroblasts / chemistry,  cytology
Hypertension / drug therapy
Hypotension / drug therapy
Matrix Metalloproteinase 2 / metabolism*
Peptide Fragments / metabolism
Peptides / chemistry,  metabolism*,  urine
Rats, Inbred Lew
Receptors, Adrenomedullin
Receptors, Peptide / metabolism
Substrate Specificity
Urine / chemistry
Vasoconstrictor Agents / metabolism*
Vasodilator Agents / metabolism*
Reg. No./Substance:
0/Peptide Fragments; 0/Peptides; 0/Receptors, Adrenomedullin; 0/Receptors, Peptide; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 148498-78-6/Adrenomedullin; 60-92-4/Cyclic AMP; EC Metalloproteinase 2
Comment In:
Biochem J. 2004 Nov 1;383(Pt. 3):e5-7   [PMID:  15508185 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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