Fluoxetine inhibits monocrotaline-induced pulmonary arterial remodeling involved in inhibition of RhoA–Rho kinase and Akt signalling pathways in rats

Wang, Hanming; Wang, Yun; Liu, Ming; Bai, Yang; Zhang, Xinhua; Sun, Yingxian; Wang, Huailiang

doi:10.1139/y2012-108

Cited by 29 publications

(26 citation statements)

References 29 publications

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“…Thus the present findings are supportive of a TG2-dependent mechanism since the SERT transporter would provide the intracellular 5-HT necessary for the serotonylation modification of AKT (Figure 7B). A role for SERT in AKT activation in vivo in a rat model of PH has been noted by others [29], and our findings here would indicate a TG2-mediated mechanism for this. An earlier report showed that 5-HT-driven AKT activation in PASMC was sensitive to 5-HT receptor (5-HTR) inhibitors [23]; however this was based on the use of only pharmacologic inhibitors, whereas the present study utilizes both pharmacologic and genetic inhibitions of SERT which support the concept that 5-HT-driven AKT also involves SERT.…”

Section: Discussionsupporting

confidence: 85%

Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells

Penumatsa¹,

Abualkhair²,

Lin³

et al. 2014

Cellular Signalling

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Tissue transglutaminase 2 (TG2) is a multifunctional enzyme that cross-links proteins with monoamines such as serotonin (5-hydroxytryptamine, 5-HT) via a transglutamidation reaction, and is associated with pathophysiologic vascular responses. 5-HT is a mitogen for pulmonary artery smooth muscle cells (PASMC) that has been linked to the pulmonary vascular remodeling underlying pulmonary hypertension development. We previously reported that 5-HT-induced PASMC proliferation is inhibited by the TG2 inhibitor monodansylcadaverine (MDC); however, the mechanisms are poorly understood. In the present study we hypothesized that TG2 contributes to 5-HT-induced signaling pathways of PASMC. Pre-treatment of bovine distal PASMC with varying concentrations of the inhibitor MDC led to differential inhibition of 5-HT-stimulated AKT and ROCK activation, while p-P38 was unaffected. Concentration response studies showed significant inhibition of AKT activation at 50 μM MDC, along with inhibition of the AKT downstream targets mTOR, p-S6 Kinase and p-S6. Furthermore, TG2 depletion by siRNA led to reduced 5-HT-induced AKT activation. Immunoprecipitation studies showed that 5-HT treatment led to increased levels of serotonylated AKT and increased TG2-AKT complex formations which were inhibited by MDC. Overexpression of TG2 point mutant cDNAs in PASMC showed that the TG2 C277V transamidation mutant blunted 5-HT-induced AKT activation and 5-HT-induced PASMC mitogenesis. Finally, 5-HT-induced AKT activation was blunted in SERT genetic knock-out rat cells, but not in their wild-type counterpart. The SERT inhibitor imipramine similarly blocked AKT activation. These results indicate that TG2 contributes to 5-HT-induced distal PASMC proliferation via promotion of AKT signaling, likely via its serotonylation. Taken together, these results provide new insight into how TG2 may participate in vascular smooth muscle remodeling.

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Section: Discussionsupporting

confidence: 85%

Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells

Penumatsa¹,

Abualkhair²,

Lin³

et al. 2014

Cellular Signalling

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“…Fluoxetine, is an inhibitor of SERT, and its inhibitory effects on pulmonary vascular remodeling in MCT-induced PAH are mediated through the downregulation of the ERK, Akt and RhoA/ROCK signaling pathways (17). In addition, fluoxetine suppresses lung tissue inflammation (17,18).…”

Section: Discussionmentioning

confidence: 99%

“…The data of pulmonary arterial pressure (PAP) and systemic arterial pressure (SAP) were kept as records under the same factors, as previously described (17,18). To measure PAP, a PV-1 catheter was inserted into the right jugular vein via the right atrium and ventricle, and was finally introduced into the pulmonary artery (16,18).…”

Section: Methodsmentioning

confidence: 99%

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The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB

Bai

Wang

et al. 2017

International Journal of Molecular Medicine

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Inflammation and remodeling play a role in the pathogenesis of pulmonary arterial hypertension (PAH). Nuclear factor-κB (NF-κB) and nuclear factor of activated T cells-1 (NFAT-1) participate in inflammation and remodeling in a number of diseases. As a tryptophan hydroxylase inhibitor, 4-chloro-DL-phenylalanine (PCPA) had been reported to exert anti-inflammatory and remodeling effects. Therefore, we hypothesized that PCPA may attenuate monocrotaline (MCT)-induced PAH through the NFAT-1 and NF-κB signaling pathways. In order to confirm our hypothesis, we divided 68 Sprague-Dawley male rats into 4 groups as follows: the control, MCT, MCT + P1 and MCT + P2 groups. MCT was administered at a dose of 60 mg/kg once via intraperitoneal injection. PCPA was administered via intraperitoneal injection at a dose of 50 or 100 mg/kg once daily for 21 consecutive days. We then measured the hemodynamic index and morphological analysis was carried out on the lung tissues. Western blot analysis and immunohistochemistry were used to examine the levels of NFAT-1 and NF-κB p-65. The expression levels of phosphorylated inhibitor of NF-κB kinase (p-IKK), IKK, phosphorylated extracellular signal-regulated kinase (p-ERK), ERK, intercellular adhesion molecule-1 (ICAM-1) and interleukin-6 (IL-6) were examined by western blot analysis. MCT was found to significantly induce PAH, with inflammation and remodeling of the lung tissues. This was associatd with an increased expression of NFAT-1, p-IKK, p-ERK and nuclear p65. PCPA significantly attenuated MCT-induced inflammation and arterial remodeling, and decreased the expression of NFAT-1, as well as that of relevant proteins of the NF-κB signaling pathway. The above-mentioned findings suggest that the inhibitory effects of PCPA on MCT-induced inflammation and arterial remodeling are related to the downregulation of the NFAT-1 and NF-κB signaling pathways in rats with PAH.

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“…Experimental treatments that have been tested in this model include serine elastase inhibition (M249314 or ZD0892), platelet-derived growth factor inhibition (imatinib), Rhokinase inhibition (fasudil), endothelin receptor antagonists (endothelin-1), serotonin transporter inhibition (fluoxetine), phosphodiesterase-5 inhibition (sildenafil and phosphodiesterase-3/4 inhibitors such as pumafentrine), statins (simvastatin, pravastatin, and rosuvastatin), and many others. [53][54][55][56][57][58][59][60][61][62][63][64] The excessive degree of improvement with these experimental treatments has been criticized in the literature because it is believed to reflect imperfect models, inadequate duration of the studies, and endpoints that do not correlate with the progression of PH observed in humans. 26,27 Gomez-Arroyo et al 24 suggest that the MCT model harbors an MCT syndrome consisting of pulmonary interstitial edema, myocarditis, and hepatic veno-oclusive disease that is uncharacteristic of severe human PH.…”

Section: The Animal Models Used In Ph Research Monocrotaline Modelmentioning

confidence: 99%

A Comprehensive Review: The Evolution of Animal Models in Pulmonary Hypertension Research; Are We there Yet?

et al. 2013

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Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans.

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Fluoxetine inhibits monocrotaline-induced pulmonary arterial remodeling involved in inhibition of RhoA–Rho kinase and Akt signalling pathways in rats

Cited by 29 publications

References 29 publications

Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells

Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells

The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB

A Comprehensive Review: The Evolution of Animal Models in Pulmonary Hypertension Research; Are We there Yet?

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