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Epidemiological data have shown that methamphetamine (MA) abuse significantly increases the risk of developing pulmonary arterial hypertension (PAH). To investigate whether MA could induce PAH and its possible mechanism, rats were exposed daily to MA for 5 weeks in the absence or presence of fluoxetine. The results showed that the pulmonary arterial pressure was not significantly increased, but the pulmonary arterial remodelling was markedly developed in the MA exposure group. The protein expressions of the serotonin transporter (5-HTT) and 5-HT(1B) receptor were increased in the lungs and in the pulmonary arteries of MA-treated rats. Fluoxetine attenuated the pulmonary arterial remodelling and down-regulated the protein expression of 5-HTT and 5-HT(1B) receptor in pulmonary arteries of MA-treated rats. These findings suggest that fluoxetine has a novel potential suppressive effect on the chronic MA-induced pulmonary vascular remodelling and also suggest that 5-HTT and 5-HT(1B) receptor may be involved as part of its mechanism., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

Activation of the small GTPase Ras homolog gene family member A (RhoA) and Rho-associated kinase (ROCK) are important in the pathogenesis of pulmonary arterial hypertension (PAH). Selective serotonin reuptake inhibitors inhibit activation of RhoA and ROCK in vitro, and ameliorate PAH and pulmonary arterial remodeling in vivo. However, little is known about whether the RhoA-ROCK signalling pathway is involved in the treatment of PAH with fluoxetine in vivo. The aim of the present study was to investigate the involvement of the RhoA-ROCK signalling pathway in the protective effect of the selective serotonin reuptake inhibitor fluoxetine against monocrotaline (MCT)-induced pulmonary arterial remodeling. MCT was applied to establish PAH in male Wistar rats. Fluoxetine was administered by gastric gavage once a day for 21 d. The results showed that MCT induced pulmonary arterial remodeling, raised the serotonylation and membrane translocation of RhoA in the lungs, and increased serotonin transporter (5-HTT), RhoA, and ROCK2 expression, and extracellular signal-regulated kinase (ERK) and Akt phosphorylation in the pulmonary arteries and the lungs. Fluoxetine markedly inhibited these MCT-induced changes. The findings suggest that fluoxetine inhibits MCT-induced pulmonary arterial remodeling in rats by inhibition of the RhoA-ROCK and Akt signalling pathways.

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.

1. Osteopontin (OPN) has emerged as a key factor in inflammatory activation and cardiovascular remodelling. The aim of the present study was to investigate the involvement of OPN in fluoxetine amelioration of monocrotaline (MCT)-induced pulmonary inflammation and vascular remodelling in rats. 2. Wistar rats were divided into control, MCT and two fluoxetine-treated groups. Pulmonary arterial hypertension (PAH) was induced by a single injection of MCT (60 mg/kg, i.p.). Fluoxetine (2 and 10 mg/kg) was administered via the intragastric route once a day for 21 days. On Day 22, pulmonary haemodynamic measurements were undertaken, followed by ELISA, western blotting and immunohistochemistry. 3. Monocrotaline caused pulmonary inflammation and vascular remodelling and significantly enhanced OPN expression in the plasma, lungs and pulmonary arteries. Fluoxetine decreased pulmonary arterial pressure and ameliorated pulmonary inflammation and pulmonary vascular remodelling. At 10 mg/kg, fluoxetine significantly inhibited MCT-induced increases in the expression of serotonin transporter (SERT) and phosphorylated extracellular signal-regulated kinase 1/2 and downregulated the expression of OPN, macrophage inflammatory protein-1β and matrix metalloproteinase 2/tissue inhibitor of metalloproteinase 2. Although 2 mg/kg fluoxetine tended to ameliorate some MCT-induced changes in the lung, the differences did not always reach statistical significance. Linear regression analysis showed that there was a positive correlation between plasma OPN concentrations and mean pulmonary arterial pressure, as well as percentage medial wall thickness and percentage wall area in the pulmonary artery. 4. In conclusion, the amelioration by fluoxetine of MCT-induced pulmonary inflammation and vascular remodelling is associated with downregulation of OPN expression in rats., (© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.)

Mutations in bone morphogenetic protein (BMP) receptor II (BMPR2) are associated with the apoptosis of the pulmonary artery endothelial cells and the loss of the pulmonary small vessels. The present study was designed to investigate the involvement of BMPR2 in the protective effect of fluoxetine against monocrotaline (MCT)-induced endothelial apoptosis in rats. Models of pulmonary arterial hypertension in rats were established by a single intraperitoneal injection of MCT (60 mg/kg). Fluoxetine (2 and 10 mg/kg) was intragastrically administered once a day. After 21 days, MCT caused pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling and significantly reduced the BMPR2 expression in lungs and pulmonary arteries. Fluoxetine dose-dependently inhibited MCT-induced pulmonary arterial hypertension and effectively protected the lungs against MCT-induced endothelial apoptosis, reduction in the number of alveolar sacs, and loss of the pulmonary small vessels. Fluoxetine reversed the expression of cyclic guanosine 3',5'-monophosphate-dependent kinase І, BMPR2, phospho-Smad1, β-catenin, and reduced the expression of caspase 3 in rat lungs. These findings suggest that BMPR2 is probably involved in the protective effect of fluoxetine against MCT-induced endothelial apoptosis in rats.

Aim: To investigate the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine on extracellular matrix (ECM) remodeling of the pulmonary artery and inflammation of the lungs in pulmonary arterial hypertension (PAH) induced by monocrotaline in rats., Methods: MCT-induced chronic PAH was established in Wistar rats. After treatment with fluoxetine for 3 weeks, pulmonary hemodynamic measurement and morphological investigation of lung tissues were undertaken. The main components of the ECM, elastin and collagen, were detected using Van Gieson stain and Orcein stain, respectively, or using Victoria-ponceau's double stain. The ECM proteolytic enzymes matrix metalloproteinase (MMP)-2 and MMP-9, and the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, were detected by Western blot. Inflammation of lung tissue was assayed using lung morphology and inflammatory cytokine expression., Results: Fluoxetine (2 and 10 mg/kg) significantly inhibited MCT-induced PAH, attenuated pulmonary arterial muscularization and ECM remodeling, and decreased MMP/TIMP expression. Fluoxetine also suppressed inflammatory responses in lung tissue and inhibited the expression of the inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein (MCP-1) and intercellular adhesion molecule-1 (ICAM-1)., Conclusion: Fluoxetine inhibited MCT-induced ECM remodeling of the pulmonary artery and inflammation of lung tissue. These effects were related to its inhibition on MMPs/TIMPs and cytokine productions.

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.

Aim: To investigate the effect of 5-hydroxytryptamine transporter (5-HTT) inhibitor fluoxetine and antisense oligodeoxynucleotide (ODN) to extracelluar signal-regulated kinases (ERKs) on pulmonary arterial smooth muscle cells (PASMCs) proliferation induced by 5-HT., Methods: Liposomal transfection was used to introduce ODNs to ERK1/2 into cultured rat PASMCs and the transfection efficiency was measured by observing the uptake of the fluorecein isothiocynate (FITC)-labeled antisense ODN in PASMCs. The effects of 5-HTT selective inhibitor fluoxetine and ODNs on the proliferation of PASMCs were evaluated by cell number counting and cell cycle analysis, and measured by microculture tetrazolium (MTT) assay and flow cytometry (FCM), respectively., Results: Liposomes mediated the transfection of ODNs into PASMCs with high efficiency. MTT assay showed fluoxetine (10 micromol/L, 1 micromol/L, and 100 nmol/L) concentration dependently inhibited the proliferation of PASMCs induced by 5-HT (1 micromol/L) in vitro. The proliferation rate of PASMCs by 5-HT was significantly inhibited by pretreatment with ERK1/2 antisense ODN (0.2 micromol/L) from 251%+/-18% to 86%+/-5% (P<0.01). Flow cytometric analysis of cell cycle distribution showed that the increase of 5-HT induced S phase fraction (SPF) and proliferation index (PI) were significantly inhibited by fluoxetine (1 micromol/L) or antisense ODN with SPF from 36%+/-4% to 26%+/-3% and 24%+/-4%, and PI from 34%+/-2% to 29%+/-2% and 24%+/-2%, respectively., Conclusion: 5-HTT mediates the mitogenic effect of 5-HT on PASMCs and the proliferation of PASMCs induced by 5-HT is dependent on ERKs signal pathway.

1. Serotonin (5-HT), as a type of mitogen for smooth muscle cells, plays an important role in the development of pulmonary hypertension. It is known that selective serotonin re-uptake inhibitors (SSRI) inhibit 5-HT internalization. Therefore, the aim of the present study was to investigate the protective effect and mechanism of the SSRI sertraline against pulmonary hypertension. 2. Monocrotaline (MCT)-induced chronic ‘inflammatory’ pulmonary hypertension in Wistar rats was established. Pulmonary haemodynamic measurement and lung tissue morphological investigations were undertaken. Serotonin transporter (SERT) mRNA was assayed by reverse transcription–polymerase chain reaction (RT-PCR). 3. The results showed that pulmonary artery pressure (PAP) was significantly increased by MCT treatment from 12.6 ± 2.1 to 20.1 ± 3.4 mmHg ( P < 0.01 vs control) and sertraline attenuated the MCT-induced increase in PAP from 20.1 ± 3.4 to 16.4 ± 1.8 mmHg ( P < 0.05 vs MCT). The right ventricular index was increased in the MCT-treated group from 0.32 ± 0.04 to 0.51 ± 0.09 ( P < 0.01 vs control) and was reduced to 0.42 ± 0.04 by sertraline ( P < 0.05 vs MCT). The degree of muscularization of the pulmonary artery in the MCT-treated group was significantly higher than control ( P < 0.01) and was decreased by sertraline ( P < 0.01 vs MCT). The RT-PCR assay showed that MCT increased SERT mRNA expression from 0.86 ± 0.08 to 0.99 ± 0.06 ( P < 0.05 vs control), which was attenuated by sertraline (0.82 ± 0.09; P < 0.05 vs MCT). 4. In conclusion, the SSRI sertraline protects against MCT-induced pulmonary hypertension by decreasing PAP, right ventricular index and pulmonary artery remodelling, which may be related to a reduction in SERT mRNA. [ABSTRACT FROM AUTHOR]