Fluoxetine protects against monocrotaline-induced pulmonary arterial hypertension: potential roles of induction of apoptosis and upregulation of Kv1.5 channels in rats.
1. Suppressing apoptosis and downregulating K(+) channels in pulmonary artery smooth muscle cells (PASMC) have been implicated in the development of pulmonary vascular medial hypertrophy and pulmonary arterial hypertension (PAH). Previous studies have shown that selective serotonin re-uptake inhibitors (SSRIs) protected against PAH. The aim of the present study was to investigate the involvement of Kv1.5 channels and apoptosis in the protective effect of the SSRI fluoxetine against PAH. 2. Monocrotaline (MCT) was used to establish PAH in Wistar rats. Fluoxetine (2 and 10 mg/kg per day) was administered by gavage once a day for 3 weeks. Three weeks after the induction of PAH by MCT, pulmonary haemodynamic measurements and pulmonary artery morphological assessments were undertaken, along with detection of apoptosis and Kv1.5. 3. Fluoxetine (2 and 10 mg/kg per day) decreased pulmonary artery pressure, reduced the right ventricular index and inhibited the increase in medial wall thickness of pulmonary arteries in established PAH. Fluoxetine (10 mg/kg per day) reduced the expression of Bcl-2 and Bcl-xL protein, increased the expression of cleaved caspase 3 protein and enhanced the expression of Kv1.5 protein and mRNA in pulmonary arteries. Furthermore, fluoxetine (10 mg/kg per day) significantly suppressed proliferation and enhanced apoptosis of PASMC in MCT-induced PAH. 4. In conclusion, fluoxetine protects against MCT-induced PAH by suppressing PASMC proliferation, inducing PASMC apoptosis and upregulating Kv1.5 channels.
Zhai
Feng-Guo
FG
Department of Clinical Pharmacology, China Medical University, Shenyang, China.
Zhang
Xin-Hua
XH
Wang
Huai-Liang
HL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000008:administration & dosage / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051666:Kv1.5 Potassium Channel / Q000096:biosynthesis*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D015854:Up-Regulation
D005473:Fluoxetine; D051666:Kv1.5 Potassium Channel; D016686:Monocrotaline; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat