title: Angiotensin-converting enzyme inhibition delays pulmonary vascular neointimal formation.
abstract: Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension.
authors.affiliation: Respiratory and Critical Care Division, Washington University Medical Center, St. Louis, Missouri, USA.
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: M L
authors.initials: ML
authors.lastname: Bernstein
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: D P
authors.initials: DP
authors.lastname: Schuster
authors.forename: M D
authors.initials: MD
authors.lastname: Botney
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D002455:Cell Division; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000473:pathology; D005240:Feasibility Studies; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006984:Hypertrophy; D017403:In Situ Hybridization; D008297:Male; D016686:Monocrotaline / Q000009:adverse effects; D009929:Organ Size; D011013:Pneumonectomy; D011042:Poisons / Q000009:adverse effects; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology; D011652:Pulmonary Circulation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014333:Tropoelastin / Q000235:genetics / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D011042:Poisons; D011347:Procollagen; D014333:Tropoelastin; D016686:Monocrotaline