Document Detail

Matrix metalloproteinase-7 and ADAM-12 (a disintegrin and metalloproteinase-12) define a signaling axis in agonist-induced hypertension and cardiac hypertrophy.
MedLine Citation:
PMID:  19398663     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Excessive stimulation of Gq protein-coupled receptors by cognate vasoconstrictor agonists induces a variety of cardiovascular processes, including hypertension and hypertrophy. Here, we report that matrix metalloproteinase-7 (MMP-7) and a disintegrin and metalloproteinase-12 (ADAM-12) form a novel signaling axis in these processes.
METHODS AND RESULTS: In functional studies, we targeted MMP-7 in rodent models of acute, long-term, and spontaneous hypertension by 3 complementary approaches: (1) Pharmacological inhibition of activity, (2) expression knockdown (by antisense oligodeoxynucleotides and RNA interference), and (3) gene knockout. We observed that induction of acute hypertension by vasoconstrictors (ie, catecholamines, angiotensin II, and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester) required the posttranscriptional activation of vascular MMP-7. In spontaneously hypertensive rats, knockdown of MMP-7 (by RNA interference) resulted in attenuation of hypertension and stopped development of cardiac hypertrophy. Quantitative reverse-transcription polymerase chain reaction studies in mouse models of MMP-7 knockdown (by RNA interference) and gene knockout revealed that MMP-7 controlled the transcription of ADAM-12, the major metalloproteinase implicated in cardiac hypertrophy. In mice with angiotensin II-induced hypertension and cardiac hypertrophy, myocardial ADAM-12 and downstream hypertrophy marker genes were overexpressed. Knockdown of MMP-7 attenuated hypertension, inhibited ADAM-12 overexpression, and prevented cardiac hypertrophy.
CONCLUSIONS: Agonist signaling of both hypertension and hypertrophy depends on posttranscriptional and transcriptional mechanisms that involve MMP-7, which is transcriptionally connected with ADAM-12. Approaches targeting this novel MMP-7/ADAM-12 signaling axis could have generic therapeutic potential in hypertensive disorders caused by multiple or unknown agonists.
Xiang Wang; Fung Lan Chow; Tatsujiro Oka; Li Hao; Ana Lopez-Campistrous; Sandra Kelly; Stephan Cooper; Jeffrey Odenbach; Barry A Finegan; Richard Schulz; Zamaneh Kassiri; Gary D Lopaschuk; Carlos Fernandez-Patron
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-04-27
Journal Detail:
Title:  Circulation     Volume:  119     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-05-12     Completed Date:  2009-06-09     Revised Date:  2014-02-07    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2480-9     Citation Subset:  AIM; IM    
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MeSH Terms
ADAM Proteins / genetics,  metabolism*
Acute Disease
Adrenergic alpha-Agonists / pharmacology
Cardiomegaly / metabolism*,  physiopathology
Disease Models, Animal
Hypertension / chemically induced,  metabolism*,  physiopathology
Matrix Metalloproteinase 7 / genetics,  metabolism*
Mice, Inbred C57BL
Mice, Mutant Strains
Norepinephrine / pharmacology
Phenylephrine / pharmacology
RNA Interference
Rats, Inbred SHR
Rats, Inbred WKY
Rats, Sprague-Dawley
Signal Transduction / physiology*
Grant Support
62718-1//Canadian Institutes of Health Research
Reg. No./Substance:
0/Adrenergic alpha-Agonists; 1WS297W6MV/Phenylephrine; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/Adam12 protein, mouse; EC 3.4.24.-/LOC100302465 protein, rat; EC Metalloproteinase 7; X4W3ENH1CV/Norepinephrine

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