Affordable Access

Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats.

Authors
  • Vieillard-Baron, Antoine
  • Frisdal, Eric
  • Raffestin, Bernadette
  • Baker, Andrew H
  • Eddahibi, Saadia
  • Adnot, Serge
  • D'Ortho, Marie-Pia
Type
Published Article
Journal
Human Gene Therapy
Publisher
Mary Ann Liebert
Publication Date
Jun 09, 2003
Volume
14
Issue
9
Pages
861–869
Identifiers
PMID: 12828857
Source
Medline
License
Unknown

Abstract

Extracellular matrix dysregulation is key to the development of pulmonary hypertension (PH), suggesting a pivotal role for the proteases that control matrix remodeling. Both hypoxia- and monocrotaline-induced PH are associated with increased protease activity in the distal and proximal pulmonary arteries. However, the role of proteases is not completely understood. In hypoxic PH, matrix metalloproteinase (MMP) inhibition increased pulmonary vascular remodeling, whereas in monocrotaline PH, serine elastase inhibition reversed pulmonary vascular remodeling. These conflicting effects of protease inhibition may be ascribable to differences across experimental models in either the mechanisms underlying PH or the methods used to inhibit protease activity. In the present study, we investigated the effects of specific MMP inhibition on monocrotaline PH development. To inhibit lung MMP in rats exposed to monocrotaline (60 mg/kg as a single subcutaneous injection), we used intratracheal instillation of the adenovirus-mediated human TIMP-1 gene (Ad.hTIMP-1, 10(8) plaque-forming units) as in our previous study on hypoxic PH. MMP inhibition in lungs was evaluated by in situ zymography. Rats treated with Ad.hTIMP-1 had less severe pulmonary vascular remodeling evidenced by a decreased right ventricular hypertrophy, with decreased muscularization of peripheral pulmonary arteries and increased lung-cell apoptosis compared to controls. No periadventitial collagen accumulation was observed in distal pulmonary arteries, whereas elastin content was significantly increased in Ad.hTIMP-1-treated rats. These data support a deleterious role for proteases in toxic and inflammatory PH and indicate that MMPs may have opposite effects in different PH models.

Report this publication

Statistics

Seen <100 times