title: Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis.
abstract: It remains unknown whether current disease-targeting therapy can histologically reverse obstructive pulmonary vasculopathy and how the timing of the therapy influences the antiremodeling effects of the compound. We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. Rats with pulmonary arterial hypertension (PAH), which were produced by combined exposure to a vascular endothelial growth factor receptor inhibitor Sugen 5416 and hypobaric hypoxia for 3 wk, were assigned to receive macitentan or vehicle during 3-5 wk (early study) or during 5-8 wk (late study) after Sugen injection. Compared with vehicle-treated PAH rats and PAH rats evaluated before treatment initiation, the macitentan-treated rats showed decreases in the proportion of occlusive lesions in the early study, a finding consistent with the reversal of right ventricular systolic pressure and indexes of right ventricular hypertrophy and medial wall thickness. Macitentan ameliorated but did not reverse the proportion of occlusive lesions in the late study. Although macitentan decreased the proportion of Ki67+ lesions in both studies, macitentan increased the proportion of cleaved caspase 3+ lesions and suppressed an antiapoptotic molecule survivin expression in the early study but not in the late study. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD.
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu City, Japan; Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shinohara
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu City, Japan;
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu City, Japan;
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Otsuki
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu City, Japan;
authors.forename: Noriko
authors.initials: N
authors.lastname: Yodoya
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu City, Japan;
authors.forename: Taichi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu City, Japan;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu City, Japan;
authors.forename: Erquan
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Saitoh
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu City, Japan; and.
authors.forename: Hideto
authors.initials: H
authors.lastname: Shimpo
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu City, Japan;
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu City, Japan;
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komada
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu City, Japan; ymitani@clin.medic.mie-u.ac.jp.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Mitani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D011743:Pyrimidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism*; D013449:Sulfonamides; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C516989:Birc5 protein, rat; D065130:Endothelin A Receptor Antagonists; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D011743:Pyrimidines; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; C533860:macitentan
keywords: apoptosis; endothelin; pathology; pulmonary hypertension