Document Detail

Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling.
MedLine Citation:
PMID:  19969080     Owner:  NLM     Status:  MEDLINE    
Structural vascular changes in two-kidney, one-clip (2K-1C) hypertension may result from increased matrix metalloproteinase (MMP)-2 activity. MMP-2 activation is regulated by other MMPs, including transmembrane-MMPs, and by tissue inhibitors of MMPs (TIMPs). We have investigated the localization of MMP-2, -9, -14, and TIMPs 1-4 in hypertensive aortas and measured their levels by zymography/Western blotting and immunohistochemistry. Gelatinolytic activity was assayed in tissues by in situ zymography. Sham-operated and 2K-1C hypertensive rats were treated with doxycycline (or vehicle) for 8 weeks, and the systolic blood pressure was monitored weekly. Doxycycline attenuated 2K-1C hypertension (165 + or - 11.7 mmHg versus 213 + or - 7.9 mm Hg in hypertensive controls, P<0.01), and completely prevented increase in the thicknesses of the media and the intima in 2K-1C animals (P<0.01). Increased amounts of MMP-2, -9, and -14 were found in hypertensive aortas, as well as enhanced gelatinolytic activity. A gradient in the localization of MMP-2, -9, and -14 was found, with increased amounts detected in the intima, at sites with higher gelatinolytic activity. Doxycycline attenuated hypertension induced increases in all the 3 investigated MMPs in both the media and the intima (all P<0.05), but it did not change the amounts of TIMPs 1-4 (P>0.05). Therefore, an imbalance between increased amounts of MMPs at the tissue level without a corresponding increase in the quantities of TIMPs, particularly in the intima and inner media layers, appears to account for the increased proteolytic activity found in 2K-1C hypertension-induced maladaptive vascular remodeling.
Michele M Castro; Elen Rizzi; Cibele M Prado; Marcos A Rossi; Jose E Tanus-Santos; Raquel Fernanda Gerlach
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-12-05
Journal Detail:
Title:  Matrix biology : journal of the International Society for Matrix Biology     Volume:  29     ISSN:  1569-1802     ISO Abbreviation:  Matrix Biol.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-05     Completed Date:  2010-07-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9432592     Medline TA:  Matrix Biol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  194-201     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier B.V. All rights reserved.
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, Brazil.
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MeSH Terms
Aorta / metabolism,  pathology
Blood Pressure / physiology
Blotting, Western
Doxycycline / pharmacology
Enzyme Inhibitors / pharmacology
Extracellular Matrix / metabolism*
Hypertension / embryology,  metabolism*,  pathology
Matrix Metalloproteinases / metabolism*
Organ Size / physiology
Rats, Wistar
Tissue Inhibitor of Metalloproteinases / metabolism*
Tunica Intima / metabolism,  ultrastructure
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Tissue Inhibitor of Metalloproteinases; 564-25-0/Doxycycline; EC 3.4.24.-/Matrix Metalloproteinases

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