MMP-2 mediates angiotensin II-induced hypertension under the transcriptional control of MMP-7 and TACE.

Abstract

Development of cardiovascular disease induced by excessive Gq protein-coupled receptor agonist stimulation depends on signaling networks involving multiple matrix metalloproteinases (MMPs) and metalloproteinase disintegrins (ADAMs). Here, we hypothesized that MMP-2, being a major gelatinase in cardiac and vascular tissue, was likely to play a key role in cardiovascular homeostasis. We targeted MMP-2 using complementary and overlapping approaches involving pharmacological inhibition and RNA interference in mice treated with angiotensin II (1.4 mg/kg per day) for 12 days. We studied the development of hypertension (by tail cuff plethysmography), cardiac hypertrophy (by M-mode echocardiography, cardiomyocyte cross-sectional area, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis of hypertrophy marker genes), and fibrosis (by picrosirius red collagen staining and qRT-PCR analysis of fibrosis marker genes) in mice receiving angiotensin II. We found that angiotensin II infusion upregulated MMP-2 concurrent with the development of hypertension, hypertrophy, and fibrosis. This upregulation of MMP-2 depended on MMP-7 and TACE (tumor necrosis factor-α convertase, ADAM-17). RNA interference targeting MMP-7 and TACE attenuated the angiotensin II-induced upregulation of MMP-2 and prevented the development of hypertension, as well as development of cardiac hypertrophy and fibrosis. In contrast, pharmacological inhibition and RNA interference of MMP-2 attenuated angiotensin II-induced hypertension, without influencing development of cardiac hypertrophy or fibrosis. Downstream of MMP-7 and TACE, MMP-2 mediated angiotensin II-induced hypertension, but did not mediate cardiac hypertrophy or fibrosis. This suggests a functional specialization of MMP-2 in agonist-induced cardiovascular disease development that has potential implications for the design of metalloproteinase-based therapeutic strategies.

• Authors: Jeffrey Odenbach, Xiang Wang, Stephan Cooper, Fung Lan Chow, Tatsujiro Oka, Gary Lopaschuk, Zamaneh Kassiri, Carlos Fernandez-Patron
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 57 Issue 1 Pg. 123-30 (Jan 2011) ISSN: 1524-4563 [Electronic] United States
• PMID: 21079048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II
• ADAM Proteins
• Matrix Metalloproteinase 7
• Matrix Metalloproteinase 2
• ADAM17 Protein
• Adam17 protein, mouse
• Adam17 protein, rat

Topics

• ADAM Proteins (metabolism)
• ADAM17 Protein
• Angiotensin II (pharmacology)
• Animals
• Cardiomegaly (enzymology, pathology)
• Fibrosis
• Gene Expression Regulation, Enzymologic
• Hypertension (enzymology, genetics)
• Male
• Matrix Metalloproteinase 2 (genetics)
• Matrix Metalloproteinase 7 (metabolism)
• Mice
• Mice, Inbred C57BL
• Myocardium (enzymology, pathology)
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• Transcription, Genetic
• Up-Regulation