FGF21 protects human umbilical vein endothelial cells against high glucose-induced apoptosis via PI3K/Akt/Fox3a signaling pathway

Guo, Dongmin; Xiao, Lele; Hu, Huijun; Liu, Mi‐Hua; Lü, Yang; Lin, Xiaolan

doi:10.1016/j.jdiacomp.2018.05.012

Cited by 27 publications

(26 citation statements)

References 31 publications

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“…Moreover, some studies describing high glucose-induced HUVECs showed results similar to ours 36. Besides the BCL-2 family, CDK1 also phosphorylates the transcription factor FOXO3a, which also leads to cell death 37. We speculate that high glucose can induce CDK1 expression in HUVECs and CDK1-related death of HUVECs involving the BCL2 family or the FOXO3a promoting signaling pathway, and that MM can maintain these pathways.…”

Section: Discussionsupporting

confidence: 81%

<p>mRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells</p>

Jin¹,

Wang²,

Pei³

et al. 2019

DMSO

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Purpose: A long-term "memory" of hyperglycemic stress, even when glycemia is normalized, has been previously reported in endothelial cells. However, the molecular mechanism of "metabolic memory" (MM) remains unknown. In this report, we sought to screen at the whole transcriptome level the genes that participate in MM. Methods: In the present research, RNA sequencing was used to determine the proteincoding mRNA expression profiles of human umbilical vein endothelial cells (HUVECs) under normal-glucose concentration (LG), high-glucose concentration (HG), and MM. A series of bioinformatic analyses was performed. HG-induced MM-involved up-regulated genes (up-HGMMGs) and HG-induced MM-involved down-regulated genes (down-HGMMGs) were identified. Afterward, based on up-HGMMGs and down-HGMMGs, the biological functions and signaling pathways were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). In addition, several of the identified genes were validated by RT-qPCR. Results: A total of 726 HGMMGs were identified, including 210 down-and 516 up-HGMMGs, which were enriched in the cell cycle (hsa04110), oocyte meiosis (hsa04114), p53 signaling pathway (hsa04115), and oxidative phosphorylation (hsa00190), among others. The protein-protein-interaction (PPI) network consisted of 462 nodes and 2656 connections, and four main modules were identified by MCODE. The cell cycle (hsa04110), oocyte meiosis (hsa04114), p53 signaling pathway (hsa04115), and oxidative phosphorylation (hsa00190), among others, could be potential therapeutic targets of HG-induced MM in endothelial cells. The real-time PCR results validated the RNA-seq data. Conclusion: This study identified crucial mRNAs related to MM-persistent injury in endothelial cells even after switching the cells from high-glucose to normal glucose levels. Further research focusing on these mRNA may unravel new ways to modify MM in diabetes.

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Section: Discussionsupporting

confidence: 81%

<p>mRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells</p>

Jin¹,

Wang²,

Pei³

et al. 2019

DMSO

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“…FGF21 is a repressor of ROS generation in multiple tissues. HUVECs pre-incubated with recombinant FGF21 were rescued from glucose-induced ROS production and cell death [ 130 ]. Another study also reported that FGF21 inhibited the oxLDL-provoked mtROS production in vascular endothelial cells [ 131 ], which provides an explanation of how these cells escape from pyroptotic cell death [ 131 , 132 ].…”

Section: Myokines and Oxidative Stressmentioning

confidence: 99%

Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle—Do Myokines Play a Role?

Pang¹,

Chan²,

Chan³

2021

Antioxidants

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Mitochondria are the cellular powerhouses that generate adenosine triphosphate (ATP) to substantiate various biochemical activities. Instead of being a static intracellular structure, they are dynamic organelles that perform constant structural and functional remodeling in response to different metabolic stresses. In situations that require a high ATP supply, new mitochondria are assembled (mitochondrial biogenesis) or formed by fusing the existing mitochondria (mitochondrial fusion) to maximize the oxidative capacity. On the other hand, nutrient overload may produce detrimental metabolites such as reactive oxidative species (ROS) that wreck the organelle, leading to the split of damaged mitochondria (mitofission) for clearance (mitophagy). These vital processes are tightly regulated by a sophisticated quality control system involving energy sensing, intracellular membrane interaction, autophagy, and proteasomal degradation to optimize the number of healthy mitochondria. The effective mitochondrial surveillance is particularly important to skeletal muscle fitness because of its large tissue mass as well as its high metabolic activities for supporting the intensive myofiber contractility. Indeed, the failure of the mitochondrial quality control system in skeletal muscle is associated with diseases such as insulin resistance, aging, and muscle wasting. While the mitochondrial dynamics in cells are believed to be intrinsically controlled by the energy content and nutrient availability, other upstream regulators such as hormonal signals from distal organs or factors generated by the muscle itself may also play a critical role. It is now clear that skeletal muscle actively participates in systemic energy homeostasis via producing hundreds of myokines. Acting either as autocrine/paracrine or circulating hormones to crosstalk with other organs, these secretory myokines regulate a large number of physiological activities including insulin sensitivity, fuel utilization, cell differentiation, and appetite behavior. In this article, we will review the mechanism of myokines in mitochondrial quality control and ROS balance, and discuss their translational potential.

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“…In contrast, a decrease of endogenous FGF21 in the liver is associated with aberrant p53 and TGF-β/ Smad signaling during hepatocellular carcinoma development [14]. Moreover, increasing evidence has demonstrated that p53 activity is negatively regulated by the activation of Akt, which is the classic downstream target enzyme of FGF21 [15].…”

Section: Introductionmentioning

confidence: 99%

Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT

Lin

et al. 2020

Diabetes Metab J

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Background: Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study. Methods: Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4´-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months. Results: DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2). Conclusion: FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.

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FGF21 protects human umbilical vein endothelial cells against high glucose-induced apoptosis via PI3K/Akt/Fox3a signaling pathway

Cited by 27 publications

References 31 publications

<p>mRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells</p>

<p>mRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells</p>

Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle—Do Myokines Play a Role?

Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT

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