title: Nanoparticle-mediated delivery of pitavastatin into lungs ameliorates the development and induces regression of monocrotaline-induced pulmonary artery hypertension.
abstract: Pulmonary artery hypertension (PAH) is an intractable disease of the small PAs in which multiple pathogenic factors are involved. Statins are known to mitigate endothelial injury and inhibit vascular remodeling and inflammation, all of which play crucial roles in the pathogenesis of PAH. We tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into the lungs can be a novel therapeutic approach for the treatment of PAH. Among the marketed statins, pitavastatin was found to have the most potent effects on proliferation of PA smooth muscle cells in vitro. We formulated pitavastatin-NP and found that pitavastatin-NP was more effective than pitavastatin alone in inhibiting cellular proliferation and inflammation in vitro. In a rat model of monocrotaline-induced PAH, a single intratracheal instillation of NP resulted in the delivery of NP into alveolar macrophages and small PAs for up to 14 days after instillation. Intratracheal treatment with pitavastatin-NP, but not with pitavastatin, attenuated the development of PAH and was associated with a reduction of inflammation and PA remodeling. NP-mediated pitavastatin delivery was more effective than systemic administration of pitavastatin in attenuating the development of PAH. Importantly, treatment with pitavastatin-NP 3 weeks after monocrotaline injection induced regression of PAH and improved survival rate. This mode of NP-mediated pitavastatin delivery into the lungs is effective in attenuating the development of PAH and inducing regression of established PAH, suggesting potential clinical significance for developing a new treatment for PAH.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Kaku
authors.initials: K
authors.lastname: Nakano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.forename: Eiko
authors.initials: E
authors.lastname: Iwata
authors.forename: Miho
authors.initials: M
authors.lastname: Miyagawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagaoka
authors.forename: Junji
authors.initials: J
authors.lastname: Kishimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008856:Microscopy, Fluorescence; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011804:Quinolines / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012074:Remission Induction
chemical_list: D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011804:Quinolines; D016686:Monocrotaline; D019001:Nitric Oxide Synthase; D016650:Fluorescein-5-isothiocyanate; C108475:pitavastatin