Peroxisome proliferator-activated receptor γ attenuates serotonin-induced pulmonary artery smooth muscle cell proliferation and apoptosis inhibition involving ERK1/2 pathway

Han, Xinyuan; Chen, Chunyan; Cheng, Gong; Liu, Liang; Yao, Xiaowei; Yang, Guang; You, Penghua; Shou, Xiling

doi:10.1016/j.mvr.2015.04.008

Cited by 15 publications

(16 citation statements)

References 34 publications

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“…42 Additionally, 5-HT has been shown to be involved in pulmonary vascular remodelling in pulmonary arterial hypertension by inducing pulmonary artery smooth muscle cell proliferation and inhibiting apoptosis. 43 Although the roles of 5-HT on different cells are diverse, excess 5-HT induced by CH and stress diarrhoea in intestine accelerated apoptosis and prevented the proliferation of enterocytes in the study. In conclusion, we demonstrated that excessive 5-HT was involved in the intestinal pathological process of stress diarrhoea.…”

Section: Discussionmentioning

confidence: 79%

The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice

et al. 2016

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Diarrhoea is a common cause of death in children and weaned animals. Recent research has found that serotonin (5-HT) in the gastrointestinal tract plays an important role in regulating growth and the maintenance of mucosa, which protect against diarrhoea. To determine the influence of 5-HT on intestinal epithelium cell renewal under weaned stress diarrhoea, a weaned-stress diarrhoea mouse model was established with senna infusion (15 mL/Kg) via intragastric administration and stress restraint (SR). Mice with an increase in 5-HT were induced by intraperitoneal injection with citalopram hydrobromide (CH, 10 mg/Kg). The results demonstrated that compared with the control animals, diarrhoea appeared in weaned stress mice and the 5-HT content in the small intestine was significantly increased (P<0.05). Further, the caspase-3 cells and cells undergoing apoptosis in the small intestine were significantly increased, but the VH (villus height), V/C (villus height /crypt depth), and PCNA-positive rate significantly decreased. Compared with the control animals, CH increased the intestinal 5-HT content, caspase-3 cells and cells undergoing apoptosis but decreased the VH and V/C. Compared with both control and weaned stress animals, weaned stress animals that were pre-treated with CH showed higher 5-HT concentrations, positive caspase-3 cells and cells undergoing apoptosis but lower VH, V/C and PCNA-positive rate. In vitro, a low concentration of 5-HT inhibit, IEC-6 cell line apoptosis but a higher concentration of 5-HT promoted it. Therefore, weaned stress diarrhoea mice were accompanied by a 5-HT increase in the small intestine and vice versa, and the increase in 5-HT induced by CH caused diarrhoea. In brief, 5-HT and diarrhoea slowed the intestinal epithelium cell renewal and injured the abortion function and mucosal barrier by decreasing VH, V/C and proliferation and increasing epithelium cell apoptosis.

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Section: Discussionmentioning

confidence: 79%

The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice

et al. 2016

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“…In contrast to VEGF and PDGF, which modulate vascular smooth muscle proliferation and differentiation through activation of tyrosine kinase receptors, other vascular growth factors act through G protein-coupled receptors to exert both acute and chronic effects on vascular smooth muscle structure and function. As for serotonin and norepinephrine (24,74), ET-1 also activates G protein-coupled receptors to produce both immediate and potent changes in vascular tone as well as longer-term changes in gene expression that influence wall thickness, smooth muscle phenotype, and contractility (18,21). Given the findings that hypoxia can increase ET-1 signaling (30) and that ET-1 can influence smooth muscle structurefunction relations (18), the present study explored the hypothesis that chronic hypoxia modulates ET-1 signaling in the fetal cerebrovasculature.…”

Section: Discussionmentioning

confidence: 99%

Chronic hypoxia alters fetal cerebrovascular responses to endothelin-1

Silpanisong

Kim

Williams

et al. 2017

American Journal of Physiology-Cell Physiology

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In utero hypoxia influences the structure and function of most fetal arteries, including those of the developing cerebral circulation. Whereas the signals that initiate this hypoxic remodeling remain uncertain, these appear to be distinct from the mechanisms that maintain the remodeled vascular state. The present study explores the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to endothelin-1 (ET-1), a potent vascular contractant and mitogen. In fetal lambs, chronic hypoxia (3,820-m altitude for the last 110 days of gestation) had no significant effect on plasma ET-1 levels or ETA receptor density in cerebral arteries but enhanced contractile responses to ET-1 in an ETA-dependent manner. In organ culture (24 h), 10 nM ET-1 increased medial thicknesses less in hypoxic than in normoxic arteries, and these increases were ablated by inhibition of PKC (chelerythrine) in both normoxic and hypoxic arteries but were attenuated by inhibition of CaMKII (KN93) and p38 (SB203580) in normoxic but not hypoxic arteries. As indicated by Ki-67 immunostaining, ET-1 increased medial thicknesses via hypertrophy. Measurements of colocalization between MLCK and SMαA revealed that organ culture with ET-1 also promoted contractile dedifferentiation in normoxic, but not hypoxic, arteries through mechanisms attenuated by inhibitors of PKC, CaMKII, and p38. These results support the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to ET-1 through pathways dependent upon PKC, CaMKII, and p38 that cause increased ET-1-mediated contractility, decreased ET-1-mediated smooth muscle hypertrophy, and a depressed ability of ET-1 to promote contractile dedifferentiation.

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“…Peroxisome proliferator-activated receptor c (PPARc) is a member of the nuclear hormone receptor superfamily (Han et al 2015) whose immunoreactivity is found in the spinal cord (Moreno et al 2004;Maeda et al 2008). Emerging evidence indicates that PPARc is involved in nociception (Maeda and Kishioka 2009).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between Cdk5/p35 and ERK1/2 signalling mediates spinal astrocyte activity via the PPARγ pathway in a rat model of chronic constriction injury

Zhong

Chen

et al. 2019

Journal of Neurochemistry

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The specific mechanisms underlying cyclin‐dependent kinase 5 (Cdk5)‐mediated neuropathic pain at the spinal cord level remain elusive. The aim of the present study was to explore the role of crosstalk between Cdk5/p35 and extracellular signal‐regulated kinase 1/2 (ERK1/2) signalling in mediating spinal astrocyte activity via the PPARγ pathway in a rat model of chronic constriction injury (CCI). Here, we quantified pain behaviour after CCI; detected the localization of p35, Cdk5, phosphorylated ERK1/2 (pERK1/2), phosphorylated peroxisome proliferator‐activated receptor γ (pPPARγ), neuronal nuclei (a neuronal marker), glial fibrillary acidic protein (GFAP, an activated astrocyte marker) and ionized calcium binding adaptor molecule 1 (a microglial marker) in the dorsal horn using immunofluorescence; measured the protein levels of Cdk5, p35, pERK1/2, pPPARγ and GFAP using western blot analysis; and gauged the enzyme activity of Cdk5/p35 kinase using a Cdk5/p35 kinase activity assay kit. Tumour necrosis factor‐α, interleukin (IL)‐1β and IL‐6 levels were measured using enzyme‐linked immunosorbent assay (ELISA). Ligation of the right sciatic nerve induced mechanical allodynia; thermal hyperalgesia; and the time‐dependent upregulation of p35, pERK1/2 and GFAP and downregulation of pPPARγ. p35 colocalized with Cdk5, pERK1/2, pPPARγ, neurons and astrocytes but not microglia. Meanwhile, intrathecal injection of the Cdk5 inhibitor roscovitine, the mitogen‐activated ERK kinase (MEK) inhibitor U0126 and the PPARγ agonist pioglitazone prevented or reversed behavioural allodynia, increased pPPARγ expression, inhibited astrocyte activation and alleviated proinflammatory cytokine (tumour necrosis factor‐α, IL‐1β, and IL‐6) release from activated astrocytes. Furthermore, crosstalk between the Cdk5/p35 and ERK1/2 pathways was observed with CCI. Blockade of either Cdk5/p35 or ERK1/2 inhibited Cdk5 activity. These findings indicate that spinal crosstalk between the Cdk5/p35 and ERK1/2 pathways mediates astrocyte activity via the PPARγ pathway in CCI rats and that targeting this crosstalk could be an effective strategy to attenuate CCI and astrocyte‐derived neuroinflammation.

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Peroxisome proliferator-activated receptor γ attenuates serotonin-induced pulmonary artery smooth muscle cell proliferation and apoptosis inhibition involving ERK1/2 pathway

Cited by 15 publications

References 34 publications

The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice

The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice

Chronic hypoxia alters fetal cerebrovascular responses to endothelin-1

Crosstalk between Cdk5/p35 and ERK1/2 signalling mediates spinal astrocyte activity via the PPARγ pathway in a rat model of chronic constriction injury

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