title: 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.affiliation: Department of Biochemistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Odenbach
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Stephan
authors.initials: S
authors.lastname: Cooper
authors.forename: Fung Lan
authors.initials: FL
authors.lastname: Chow
authors.forename: Tatsujiro
authors.initials: T
authors.lastname: Oka
authors.forename: Gary
authors.initials: G
authors.lastname: Lopaschuk
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Patron
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D000804:Angiotensin II; D051722:ADAM Proteins; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat