Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

Liu, Bing; Wang, Zhipeng; Li, Jing; Ban, Yiqian; Mao, Guangmei; Zhang, Man; Wang, Mo; Liu, Yan; Zhao, Beibei; Shen, Qiang; Xu, Qingbo; Wang, Nanping

doi:10.1161/jaha.117.006810

Cited by 17 publications

(8 citation statements)

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“…Activation of 5-HT 2B R stimulates classical Gq protein pathways and β-arrestins-dependent signaling, leading to diverse functions [ 53 , 54 ]. We explored the possible roles of these two signaling pathways in the effects of fluoxetine on A1 astrocyte reactivity.…”

Section: Resultsmentioning

confidence: 99%

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/β-arrestin2 pathway

Fang

Ding

Zhang

et al. 2022

J Neuroinflammation

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Background Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to directly bind with 5-HT2B receptor (5-HT2BR), but the precise mechanisms, whereby fluoxetine confers the anti-depressive actions via 5-HT2BR is not fully understood. Although neuroinflammation-induced A1 astrocytes are involved in neurodegenerative diseases, the role of A1 astrocyte in the pathogenesis and treatment of major depressive disorder (MDD) remains unclear. Methods Mice were subjected to chronic mild stress (CMS) for 6 weeks and subsequently treated with fluoxetine for 4 weeks. The depressive-like and anxiety-like behaviors and the activation of A1 reactive astrocyte in hippocampus and cortex of mice were measured. Primary astrocytes were stimulated with A1 cocktail (tumor necrosis factor (TNF)-α, interleukin (IL)-1α and C1q), activated (LPS) microglia-conditioned medium (MCM) or IL-6 for 24 h and the expression of A1-special and A2-special markers were determined using RT-qPCR and western blot. The role of 5-HT2BR in the effects of fluoxetine on A1 reactive astrocyte was measured using 5-HT2BR inhibitor and siRNA in vitro and AAVs in vivo. The functions of downstream signaling Gq protein and β-arrestins in the effects of fluoxetine on the activation of A1 astrocyte were determined using pharmacological inhibitor and genetic knockout, respectively. Results In this study, we found that fluoxetine inhibited the activation of A1 reactive astrocyte and reduced the abnormal behaviors in CMS mice, as well as ameliorated A1 astrocyte reactivity under three different stimulators in primary astrocytes. We also showed that astrocytic 5-HT2BR was required in the inhibitory effects of fluoxetine on A1 reactive astrocyte in MDD in vivo and in vitro. We further found that the functions of fluoxetine in the activation of A1 astrocyte were independent of either Gq protein or β-arrestin1 in vitro. β-arrestin2 pathway was the downstream signaling of astrocytic 5-HT2BR mediated the inhibitory effects of fluoxetine on A1 astrocyte reactivity in primary astrocytes and CMS mice, as well as the improved roles of fluoxetine in behavioral impairments of CMS mice. Conclusions These data demonstrate that fluoxetine restricts reactive A1 astrocyte via astrocytic 5-HT2BR/β-arrestin2 pathway in a mouse model of MDD and provide a novel therapeutic avenue for MDD.

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Section: Resultsmentioning

confidence: 99%

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/β-arrestin2 pathway

Fang

Ding

Zhang

et al. 2022

J Neuroinflammation

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“…Tryptophan is an essential amino acid that can serve as a substrate for serotonin. In vitro, serotonin significantly enhanced the proliferation and migration of rat aortic SMCs (140). It also induced PAMSC proliferation through the activation of ERK1/2 and generation of ROS, and the latter is partly mediated by NOX (100,129).…”

Section: Amino Acid Metabolismmentioning

confidence: 89%

Metabolism of vascular smooth muscle cells in vascular diseases

Shi

Yang

Cheng

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

218

120

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Vascular smooth muscle cells (VSMCs) are the fundamental component of the medial layer of arteries and are essential for arterial physiology and pathology. It is becoming increasingly clear that VSMCs can alter their metabolism to fulfill the bio-energetic and biosynthetic requirements. During vascular injury, VSMCs switch from a quiescent "contractile" phenotype to a highly migratory and proliferative "synthetic" phenotype. Recent studies find that the phenotype switching of VSMCs is driven by a metabolic switch. Metabolic pathways, including aerobic glycolysis, fatty acid oxidation, and amino acid metabolism, have distinct, indispensable roles in normal and dysfunctional vasculature. VSMCs metabolism is also related to the metabolism of endothelial cells. In the present review, we present a brief overview of VSMCs metabolism, and how it regulates the progression of several vascular diseases, including atherosclerosis, systemic hypertension, diabetes, pulmonary hypertension, vascular calcification, and aneurysms, and the effect of the risk factors for vascular disease (aging, cigarette smoking and excessive alcohol drinking) on VSMCs metabolism, to clarify the role of VSMCs metabolism in the key pathological process.

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“…The transgenic mice with serotonin transporter ( 5HTT ) overexpression in SMC exhibit the mTOR profile similar to hypoxic mice characterized by marked increases in mTORC1 and mTORC2 substrates [ 75 ]. Although other studies suggest that serotonin realizes its mitogenic effects on PASMC through AKT/mTORC1/S6K, it is still unclear whether mTORC1 activation precedes mTORC2 activation in 5HTT -transgenic mice [ 91 , 92 ]. In contrast to this, disturbed mTORC2 pathway is able to stimulate cell proliferation under certain conditions.…”

Section: Introductionmentioning

confidence: 99%

mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target

Babicheva

Makino

Yuan

2021

IJMS

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Pulmonary arterial hypertension (PAH) is a progressive and fatal disease without a cure. The exact pathogenic mechanisms of PAH are complex and poorly understood, yet a number of abnormally expressed genes and regulatory pathways contribute to sustained vasoconstriction and vascular remodeling of the distal pulmonary arteries. Mammalian target of rapamycin (mTOR) is one of the major signaling pathways implicated in regulating cell proliferation, migration, differentiation, and protein synthesis. Here we will describe the canonical mTOR pathway, structural and functional differences between mTOR complexes 1 and 2, as well as the crosstalk with other important signaling cascades in the development of PAH. The pathogenic role of mTOR in pulmonary vascular remodeling and sustained vasoconstriction due to its contribution to proliferation, migration, phenotypic transition, and gene regulation in pulmonary artery smooth muscle and endothelial cells will be discussed. Despite the progress in our elucidation of the etiology and pathogenesis of PAH over the two last decades, there is a lack of effective therapeutic agents to treat PAH patients representing a significant unmet clinical need. In this review, we will explore the possibility and therapeutic potential to use inhibitors of mTOR signaling cascade to treat PAH.

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Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

Cited by 17 publications

References 83 publications

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/β-arrestin2 pathway

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/β-arrestin2 pathway

Metabolism of vascular smooth muscle cells in vascular diseases

mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target

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