title: Fluoxetine protects against monocrotaline-induced pulmonary arterial remodeling by inhibition of hypoxia-inducible factor-1α and vascular endothelial growth factor.
abstract: The selective serotonin re-uptake inhibitor fluoxetine has been shown to protect against monocrotaline (MCT)-induced pulmonary hypertension in rats. To investigate the possible role of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in mediating this protective effect, MCT-treated rats were administered fluoxetine by gavage, at doses of 2 mg/kg body mass or 10 mg/kg once daily for 3 weeks. Changes in pulmonary hemodynamic parameters, pulmonary artery morphologies, and expressions of HIF-1α and VEGF were assessed. Fluoxetine at the 10 mg/kg  dose, but not at the 2 mg/kg dose, attenuated the effects of MCT on pulmonary artery pressure, right ventricle index, and medial wall thickness. In addition, 10 mg/kg fluoxetine mitigated the MCT-induced up-regulation of HIF-1α and VEGF protein and reactive oxygen species (ROS) in the lungs. This dosage also decreased pERK1/2 levels and inhibited proliferation of pulmonary arterial smooth muscle cells in MCT-treated rats. In conclusion, fluoxetine can protect against MCT-induced pulmonary arterial remodeling, which linked to reduced ROS generation and decreased HIF-1α and VEGF protein levels via the ERK1/2 phosphorylation pathway.
authors.affiliation: Department of Clinical Pharmacology, China Medical University, Heping District, Shenyang, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Han
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.forename: Jin-Rong
authors.initials: JR
authors.lastname: Liu
authors.forename: Huai-Liang
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology* / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006984:Hypertrophy / Q000188:drug therapy; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D000959:Antihypertensive Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D005473:Fluoxetine; D016686:Monocrotaline