© 2000 American Heart Association, Inc.
Integrative Physiology |
Inhibition of Matrix Metalloproteinases by Lung TIMP-1 Gene Transfer or Doxycycline Aggravates Pulmonary Hypertension in Rats
From INSERM U492 (A.V.-B., E.F., S.E., I.D., M.L., B.R., S.A., M.-P.d’O.), Faculté de Médecine, Créteil, France; Service de Réanimation Médicale (A.V.-B.) and Service des Explorations Fonctionnelles (B.R.), Hôpital Ambroise Paré, AP-HP, Boulogne, France; Bristol Heart Institute (A.H.B., A.C.N.), University of Bristol, Bristol Royal Infirmary, Bristol, UK; INSERM E-9937 (P.B.), Université Victor Segalen Bordeaux 2, Bordeaux, France; and Service des Explorations Fonctionnelles (S.A., M.-P.d’O.), Hôpital Henri Mondor, AP-HP, Créteil, France.
Correspondence to Marie-Pia d’Ortho, INSERM U492, 8 rue du Général Sarrail, 94010 Creteil, France. E-mail dortho{at}im3.inserm.fr
Abstract—Chronic hypoxic pulmonary hypertension (PH) results from persistent vasoconstriction, excess muscularization, and extracellular matrix remodeling of pulmonary arteries. The matrix metalloproteinases (MMPs) are a family of proteinases implicated in extracellular matrix turnover and hence in smooth muscle and endothelial cell migration and proliferation. Because MMP expression and activity are increased in PH, we designed the present study to investigate whether inhibition of lung MMPs in rats subjected to chronic hypoxia (CH) contributes to or protects against vascular remodeling and PH. To achieve lung MMP inhibition, rats exposed to 10% O2 for 15 days were treated with either doxycycline (20 mg/kg per day by gavage starting 2 days before and continuing throughout the CH period) or a single dose of recombinant adenovirus (Ad) for the human tissue inhibitors of metalloproteinases-1 (hTIMP-1) gene (Ad.hTIMP-1, 108 plaque-forming units given intratracheally 2 days before CH initiation). Control groups either received no treatment or were treated with an adenovirus containing no gene in the expression cassette (Ad.Null). Efficacy of hTIMP-1 gene transfer was assessed both by ELISA on bronchoalveolar lavages and by hTIMP-1 immunofluorescence on lung sections. MMP inhibition in lungs was evaluated by in situ zymography and gelatinolytic activity assessment using [3H]gelatin. Rats treated with either doxycycline or Ad.hTIMP-1 had higher pulmonary artery pressure and right heart ventricular hypertrophy more severe than their respective controls. Worsening of PH was associated with increased muscularization and periadventitial collagen accumulation in distal arteries. In conclusion, our study provides compelling evidence that MMPs play a pivotal role in protecting against pulmonary artery remodeling.
Key Words: pulmonary hypertension • gene therapy • inhibitor of metalloproteinases • extracellular matrix • vascular remodeling
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