Document Detail

Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure.
MedLine Citation:
PMID:  22689745     Owner:  NLM     Status:  MEDLINE    
Age-associated arterial remodeling involves arterial wall collagen deposition and elastin fragmentation, as well as an increase in arterial pressure. This arterial remodeling is linked to proinflammatory signaling, including transforming growth factor-β1, monocyte chemoattractant protein 1, and proendothelin 1, activated by extracellular matrix metalloproteinases (MMPs) and orchestrated, in part, by the transcriptional factor ets-1. We tested the hypothesis that inhibition of MMP activation can decelerate the age-associated arterial proinflammation and its attendant increase in arterial pressure. Indeed, chronic administration of a broad-spectrum MMP inhibitor, PD166739, via a daily gavage, to 16-month-old rats for 8 months markedly blunted the expected age-associated increases in arterial pressure. This was accompanied by the following: (1) inhibition of the age-associated increases in aortic gelatinase and interstitial collagenase activity in situ; (2) preservation of the elastic fiber network integrity; (3) a reduction of collagen deposition; (4) a reduction of monocyte chemoattractant protein 1 and transforming growth factor-β1 activation; (5) a diminution in the activity of the profibrogenic signaling molecule SMAD-2/3 phosphorylation; (6) inhibition of proendothelin 1 activation; and (7) downregulation of expression of ets-1. Acute exposure of cultured vascular smooth muscle cells in vitro to proendothelin 1 increased both the transcription and translation of ets-1, and these effects were markedly reduced by MMP inhibition. Furthermore, infection of vascular smooth muscle cells with an adenovirus harboring a full-length ets-1 cDNA increased activities of both transforming growth factor-β1 and monocyte chemoattractant protein 1. Collectively, our results indicate that MMP inhibition retards age-associated arterial proinflammatory signaling, and this is accompanied by preservation of intact elastin fibers, a reduction in collagen, and blunting of an age-associated increase in blood pressure.
Mingyi Wang; Jing Zhang; Richard Telljohann; Liqun Jiang; James Wu; Robert E Monticone; Kapil Kapoor; Mark Talan; Edward G Lakatta
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2012-06-11
Journal Detail:
Title:  Hypertension     Volume:  60     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-20     Completed Date:  2012-12-13     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  459-66     Citation Subset:  IM    
Laboratory of Cardiovascular Science, Intramural Research Program, 5600 Nathan Shock Dr, National Institute on Aging-National Institutes of Health, Baltimore, MD 21030, USA.
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MeSH Terms
Aging / metabolism*
Arteritis / metabolism,  physiopathology,  prevention & control*
Blood Pressure / drug effects,  physiology
Chemokine CCL2 / metabolism
Collagen / metabolism
Disease Models, Animal
Elastin / metabolism
Endothelin-1 / metabolism
Enzyme Inhibitors / pharmacology*
Gelatinases / metabolism
Hydroxamic Acids / pharmacology*
Hypertension / physiopathology,  prevention & control*
Matrix Metalloproteinase Inhibitors*
Matrix Metalloproteinases / drug effects*
Oligopeptides / pharmacology*
Protein Precursors / metabolism
Proto-Oncogene Protein c-ets-1 / metabolism
Rats, Inbred BN
Rats, Inbred F344
Transforming Growth Factor beta1 / metabolism
Grant Support
Z01 AG000240-01/AG/NIA NIH HHS
Reg. No./Substance:
0/(R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid; 0/Ccl2 protein, rat; 0/Chemokine CCL2; 0/Endothelin-1; 0/Enzyme Inhibitors; 0/Ets1 protein, rat; 0/Hydroxamic Acids; 0/Matrix Metalloproteinase Inhibitors; 0/Oligopeptides; 0/Protein Precursors; 0/Proto-Oncogene Protein c-ets-1; 0/Transforming Growth Factor beta1; 0/proendothelin 1; 9007-34-5/Collagen; 9007-58-3/Elastin; EC 3.4.24.-/Gelatinases; EC 3.4.24.-/Matrix Metalloproteinases

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