Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

Perl, András

doi:10.1038/nrrheum.2015.172

Cited by 271 publications

(247 citation statements)

References 236 publications

(312 reference statements)

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“…5B). AKT is the upstream factor of mTOR to together form an AKT/mTOR signaling pathway involved in metabolism regulation [13]. As shown in Fig.…”

Section: Autophagy Regulation Is Dependent On the Akt /Mtor Signalingmentioning

confidence: 99%

Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy

An¹,

Wei

et al. 2018

Cell Physiol Biochem

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Background/Aims: The phenotype switching of vascular smooth muscle cells (VSMCs) was associated with the onset or progression of the atherogenic process in type 2 diabetes mellitus (T2DM). Alprostadil (Prostaglandin E1, PGE1) as a bioactive drug had a protective effect on vascular function. However, it is unknown whether PGE1 inhibited the phenotype switching in VSMCs via autophagy, which played a protective role in the vascular complications of diabetes. Methods: The phenotype switching was induced by high glucose (HG, 25mM) in VSMCs, the protein expression was measured by western blot analysis and immunofluorescent staining. In vivo study, vascular lesion and dysfunction were produced in the rats fed with high fat diet (HFD) combined with low dose streptozotocin (STZ) administration. Results: The decrease of α-SMA and the increase of vimentin, collagen I and proliferating cell nuclear antigen (PCNA) were found in HG-treated VSMCs. Along with more abundance of p62, autophagy markers LC3B and Beclin-1 significantly decreased in VSMCs exposed to HG. Such abnormal changes were significantly reversed by PGE1, which mimicked the role of autophagy activator rapamycin and was dramatically counteracted by 3-methyladenine, an autophagy inhibitor. Furthermore, PGE1 suppressed the phosphorylation of AKT and mTOR, which negatively regulated autophagy level in VSMCs. In vivo study, PGE1 remarkably improved the endothelium-independent contraction of thoracic aorta and restored the expression of α-SMA, osteopontin, LC3B, phosphorylated mTOR in the artery media of T2DM rats. Conclusion: These results demonstrated that PGE1 maintained the phenotype of VSMCs via the AKT/mTOR-dependent autophagy, which prevented diabetes-induced vascular complications.

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“…5B). AKT is the upstream factor of mTOR to together form an AKT/mTOR signaling pathway involved in metabolism regulation [13]. As shown in Fig.…”

Section: Autophagy Regulation Is Dependent On the Akt /Mtor Signalingmentioning

confidence: 99%

Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy

An¹,

Wei

et al. 2018

Cell Physiol Biochem

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“…Inhibiting mTOR activity thwarts the generation of Th1 and Th17 effector T cells (21), but perhaps paradoxically can also enhance frequencies of cytotoxic T cells (22). Moreover, rapamycin treatment prevents and reverses lupuslike symptoms in (NZB×NZW)F 1 (NZB/W) mice (23,24), and this effect has been attributed mainly to the critical role played by mTOR signaling in effector T cell differentiation (25).…”

Section: Introductionmentioning

confidence: 99%

mTOR has distinct functions in generating versus sustaining humoral immunity

Jones¹,

Gaudette²,

Wilmore³

et al. 2016

Journal of Clinical Investigation

137

135

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. multiple comparisons, the Kruskal-Wallis test was used with Dunn's multiple comparison test. For qRT-PCR studies, the Shapiro-Wilk test was used to confirm a normal distribution for the resulting data. In each case, P values less than 0.05 were considered significant. Study approval. All animal studies described herein were reviewed and approved by the University of Pennsylvania IACUC. Animals were bred and maintained in accordance with institutional guidelines for animal welfare.

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“…Rictor is an important component of mammalian target of rapamycin complex 2 (mTORC2) and the activation of the mTORC2 depends on the presence of the Rictor protein [21]. As the Akt/eNOS signaling pathway has been reported to be activated by mTORC2 and involved in modulating ECs apoptosis, we further elucidated whether Akt/eNOS signaling pathway was involved in the action of miR-142-3p.…”

Section: Involvement Of Akt/enos Signaling Pathway In the Mir-142-3p-mentioning

confidence: 96%

MicroRNA-142-3p Induces Atherosclerosis-Associated Endothelial Cell Apoptosis by Directly Targeting Rictor

Qin

Shu

Long

et al. 2018

Cell Physiol Biochem

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Background/Aims: Atherosclerosis, a multifactorial chronic disease, is the main cause of death and impairment in the world. Endothelial cells (ECs) apoptosis plays a crucial role in the onset and development of atherosclerosis, whereas the underlying molecular mechanisms are unclear. MicroRNA-142-3p (miR-142-3p) is a well-defined tumor suppressor in several types of cancer, while the role of miR-142-3p in ECs apoptosis and the development of atherosclerosis has yet to be elucidated. Therefore, the present study aimed to investigate the role of miR-142-3p in ECs apoptosis during atherosclerosis and the underlying mechanism. Methods: Human aortic endothelial cells (HAECs) were treated with oxidized low-density lipoprotein (ox-LDL). The expression level of miR-142-3p was detected using qRT-PCR. Apoptosis was determined via flow cytometry and Caspase-3 activity assay. Prediction of the binding between miR-142-3p and 3’-UTR of Rictor mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-142-3p on endothelial apoptosis and atherosclerosis were further analyzed in an in vivo model using ApoE^-/- mice fed with high-fat diet (HFD). Results: MiR-142-3p expression was substantially up-regulated during the ox-LDL-elicited apoptosis in HAECs. Forced expression of miR-142-3p exacerbated apoptosis in ECs whereas inhibition of miR-142-3p could partly alleviate apoptotic cell death mediated by ox-LDL. Further analysis identified Rictor as a direct target of miR-142-3p, and Rictor knockdown abolished the anti-apoptotic effect of miR-142-3p inhibitor. Moreover, the Akt/endothelial nitric oxide synthase (eNOS) signaling pathway was found to mediate the beneficial effect of miR-142-3p inhibitor on endothelial apoptosis. Finally, systemic treatment with miR-142-3p antagomir attenuated endothelial apoptosis and retarded the progression of atherosclerosis in the aorta of ApoE^-/- mice. Conclusions: Down-regulation of miR-142-3p inhibited ECs apoptosis and atherosclerotic development by up-regulating the expression of Rictor and activating the Akt/eNOS signaling pathway. This indicates that miR-142-3p may be a potential target for the prevention and treatment of atherosclerosis.

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Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

Cited by 271 publications

References 236 publications

Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy

Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy

mTOR has distinct functions in generating versus sustaining humoral immunity

MicroRNA-142-3p Induces Atherosclerosis-Associated Endothelial Cell Apoptosis by Directly Targeting Rictor

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