Matrix metalloproteinase-7 and ADAM-12 (a disintegrin and metalloproteinase-12) define a signaling axis in agonist-induced hypertension and cardiac hypertrophy.

Abstract

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.

• Authors: 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
• Journal: Circulation (Circulation) Vol. 119 Issue 18 Pg. 2480-9 (May 12 2009) ISSN: 1524-4539 [Electronic] United States
• PMID: 19398663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-Agonists
• Phenylephrine
• ADAM Proteins
• ADAM12 Protein
• ADAM12 protein, rat
• Adam12 protein, mouse
• Matrix Metalloproteinase 7
• Norepinephrine

Topics

• ADAM Proteins (genetics, metabolism)
• ADAM12 Protein
• Acute Disease
• Adrenergic alpha-Agonists (pharmacology)
• Animals
• Cardiomegaly (metabolism, physiopathology)
• Disease Models, Animal
• Hypertension (chemically induced, metabolism, physiopathology)
• Matrix Metalloproteinase 7 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Norepinephrine (pharmacology)
• Phenylephrine (pharmacology)
• RNA Interference
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Rats, Sprague-Dawley
• Signal Transduction (physiology)