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Fluoxetine protects against monocrotaline-induced pulmonary arterial remodeling by inhibition of hypoxia-inducible factor-1α and vascular endothelial growth factor.
- Source :
-
Canadian journal of physiology and pharmacology [Can J Physiol Pharmacol] 2012 Apr; Vol. 90 (4), pp. 445-54. Date of Electronic Publication: 2012 Mar 26. - Publication Year :
- 2012
-
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.
- Subjects :
- Animals
Antihypertensive Agents pharmacology
Antihypertensive Agents therapeutic use
Cell Proliferation drug effects
Disease Models, Animal
Hemodynamics drug effects
Hemodynamics physiology
Hypertension, Pulmonary chemically induced
Hypertension, Pulmonary metabolism
Hypertension, Pulmonary physiopathology
Hypertrophy drug therapy
Lung drug effects
Lung metabolism
MAP Kinase Signaling System drug effects
MAP Kinase Signaling System physiology
Male
Monocrotaline
Myocytes, Smooth Muscle drug effects
Myocytes, Smooth Muscle physiology
Pulmonary Artery metabolism
Pulmonary Artery pathology
Pulmonary Artery physiopathology
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species metabolism
Fluoxetine pharmacology
Fluoxetine therapeutic use
Hypertension, Pulmonary drug therapy
Hypoxia-Inducible Factor 1, alpha Subunit biosynthesis
Pulmonary Artery drug effects
Vascular Endothelial Growth Factor A biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1205-7541
- Volume :
- 90
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Canadian journal of physiology and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 22448962
- Full Text :
- https://doi.org/10.1139/Y2012-011