Chronic matrix metalloproteinase inhibition retards age-Associated arterial proinflammation and increase in blood pressure

Mingyi Wang, Jing Zhang, Richard Telljohann, Liqun Jiang, James Wu, Robert E. Monticone, Kapil Kapoor, Mark Talan, Edward Lakatta

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)459-466
Number of pages8
JournalHypertension
Volume60
Issue number2
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

Matrix Metalloproteinases
Chemokine CCL2
Transforming Growth Factors
Blood Pressure
Arterial Pressure
Collagen
Elastin
Vascular Smooth Muscle
Smooth Muscle Myocytes
Gelatinases
Matrix Metalloproteinase 1
Elastic Tissue
Matrix Metalloproteinase Inhibitors
Adenoviridae
Extracellular Matrix
Down-Regulation
Complementary DNA
Phosphorylation
Infection
proendothelin 1

Keywords

  • aging
  • arterial remodeling
  • blood pressure
  • endothelin 1
  • ets-1
  • matrix metalloproteinase inhibitor
  • monocyte chemoattractant protein 1
  • transforming growth factor-β1

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Chronic matrix metalloproteinase inhibition retards age-Associated arterial proinflammation and increase in blood pressure. / Wang, Mingyi; Zhang, Jing; Telljohann, Richard; Jiang, Liqun; Wu, James; Monticone, Robert E.; Kapoor, Kapil; Talan, Mark; Lakatta, Edward.

In: Hypertension, Vol. 60, No. 2, 08.2012, p. 459-466.

Research output: Contribution to journalArticle

Wang, Mingyi ; Zhang, Jing ; Telljohann, Richard ; Jiang, Liqun ; Wu, James ; Monticone, Robert E. ; Kapoor, Kapil ; Talan, Mark ; Lakatta, Edward. / Chronic matrix metalloproteinase inhibition retards age-Associated arterial proinflammation and increase in blood pressure. In: Hypertension. 2012 ; Vol. 60, No. 2. pp. 459-466.
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AU - Talan, Mark

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