Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia

Dai, Xiaozhen; Yan, Xiaoqing; Zeng, Jun; Chen, Jing; Wang, Yuehui; Chen, Jun; Li, Yan; Barati, Michelle T.; Wintergerst, Kupper A.; Pan, Kehou; Nystoriak, Matthew A.; Conklin, Daniel J.; Rokosh, Gregg; Li, Xiaokun; Tan, Yi

doi:10.1161/circresaha.117.310619

Cited by 131 publications

(223 citation statements)

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“…Circulating endothelial progenitor cells (EPCs) produced in the bone marrow have the potential for multiple differentiation and initial high proliferative ability. Moreover, they can differentiate into precursor cells of mature endothelial cells (ECs) [14]. Typically, there are few EPCs in the blood circulation.…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

Deng¹,

Xu²,

Li³

et al. 2018

Oncotarget

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Background: Endothelial progenitor cell play a vital role in neovascularization. Exercise-based cardiac rehabilitation significantly increases endothelial progenitor cells number and functions in patients with ischemic disease. Exercise can also increase the level of endothelial microRNAs. We hypothesized that microRNAs participate in regulating endothelial progenitor cell function under aerobic exercise. Thus, we attempted to identify such microRNAs and to verify the miR-126-3p target gene.Methods: Microarray is used to screen the microRNAs. The prediction programs TargetScan is used to predict the miR-126-3p target gene. Experimental EPCs are treated with miR-126-3p mimics. The relative expression of miR-126-3p and Mus musculus sprouty-related EVH1 domain-containing 1 (Spred1) are examined using real-time PCR and western blot. The dual-luciferase reporter assay is used to verify the miR-126-3p target gene.Results: The miR-126-3p target genes included those contributing to angiogenesis and revascularization. The predicted miR-126-3p target gene is Spred1. Compared with the control, miR-126-3p relative expression is highest following 48-h treatment with 50 nM miR-126-3 mimic. Spred1 mRNA and protein expression in the experimental group is 40.7% and 45.7%. The ratio of Renilla and firefly luciferase activity in the wild-type group is 88.3% and 74.2% of the control respectively (all, n = 3, p < 0.001).Conclusion: miR-126-3p participates in regulating endothelial progenitor cell function after aerobic exercise. MiR-126-3p inhibits the transcription and translation of Spred1, the target gene of miR-126-3p.

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Section: Introductionmentioning

confidence: 99%

“…Then, they differentiate and form neovascularization [15]. By increasing EC number and function, c [16,17]. Moreover, we previously showed that exercise training can significantly increase EPC function and number in MI and non-MI mice via the AKT/glycogen synthase kinase 3β (GSK3β) signaling pathway [18].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

Deng¹,

Xu²,

Li³

et al. 2018

Oncotarget

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“…Endothelial progenitor cells (EPCs), recruited from the bone marrow and circulating in the peripheral blood, have the capability to differentiate into endothelial cells and seem to play a pivotal role for the repair of endothelium and to improve neovascularization (Schmidt-Lucke et al, 2005;Westerweel et al, 2013;Abplanalp et al, 2016). Diabetes mellitus, cardiovascular disease and metabolic syndrome reduce the mobilization, proliferation as well as the angiogenesis function of EPCs (Wu et al, 2016;Dai et al, 2017;Goligorsky, 2017). Diabetes mellitus, cardiovascular disease and metabolic syndrome reduce the mobilization, proliferation as well as the angiogenesis function of EPCs (Wu et al, 2016;Dai et al, 2017;Goligorsky, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…However, EPCs are susceptible to adverse environments in vivo. Diabetes mellitus, cardiovascular disease and metabolic syndrome reduce the mobilization, proliferation as well as the angiogenesis function of EPCs (Wu et al, 2016;Dai et al, 2017;Goligorsky, 2017). Interestingly, some studies further demonstrated that the EPCs senescence was accelerated in T2DM patients, which may be responsible for a limitation of self-renewal ability in EPCs and consequently reduce the neovascularization (Edelberg et al, 2002;Hibbert et al, 2014;Lee and Poh, 2014;Yiu and Tse, 2014;Yuan et al, 2015;Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC‐1α/SIRT1 signaling pathway

Song

Yang

Qiu

et al. 2017

Cell Biology International

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The objective of the research was to investigate the function of endothelial progenitor cells (EPCs) in the conditions of high glucose and lipids, which has been widely used to mimic the metabolic disorder that occurs in type 2 diabetic mellitus, and further to verify the role of PGC-1α and SIRT1, cellular energy metabolism regulators, in the process of senescence of EPCs with these combined stimuli. Circulating EPCs were incubated in absence or presence of high glucose (25 mM), FFA (200 µM) or both. EPCs senescence was assessed by β-galactosidase staining, EPCs telomerase activity was measured by telomeric repeat ampli-fication protocol assay, in vitro angiogenesis assay and MTT assays were performed to assess angiogenesis and proliferation ability of EPCs. The results showed that combined stimuli inhibited EPCs reendothelialization ability in vitro, accelerated EPCs senescence and decreased the telomerase activity. Meanwhile, with combined stimuli, the expression of PGC-1α increased whereas SIRT1 expression decreased in EPCs accompanied by activation of P53/P21 signaling pathway. Conversely, transfection of EPCs with PGC-1α-siRNA rescued EPCs premature senescence and up-regulated SIRT1 and decreased P53/P21 expression, correlating closely with the down-regulation of PGC-1α itself. In addition, the combined stimuli induced up-regulation of PGC-1α expression was partly mediated by ROS and P38 signaling pathway. Overall, the data presented here identify PGC-1α as a potent negative regulator of EPCs' senescence under combined stimuli, which is partly mediated by SIRT1/P53/P21 signaling pathway.

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“…Nrf2 mainly binds to antioxidant response element (ARE) to regulate its target genes, such as NAD(P)H quinone oxidase 1 (NQO1), heme oxygenase 1 (HO1) (132,133) . The potential protective roles of Nrf2-mediated antioxidant activation in diabetic complications, such as diabetic nephropathy, cardiomyopathy and limb ischemia, have been widely studied (134)(135)(136) .…”

Section: The Role Of Nuclear Factor E2-related Factor 2 In Diseasesmentioning

confidence: 99%

A novel fibroblast growth factor 1 variant reverses nonalcoholic fatty liver disease in type 2 diabetes.

Lin¹

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with type 2 diabetes (T2D). Our recently engineered FGF1 partial agonist, carrying triple mutations (FGF1 △ HBS) exhibits greatly reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1. This study tests the preventive and therapeutic effects of FGF1 △ HBS on NAFLD in db/db T2D and explores potential mechanisms. The results showed that administration of FGF1 △ HBS to 2-monthold db/db mice for 2 months constantly lowered blood glucose levels, improved insulin sensitivity, and lowered liver weight, lipid deposition, and inflammation, along with improvement of liver function. Simultaneously, FGF1 △ HBS treatment prevented diabetesinduced hepatic oxidative stress along with promoting nuclear translocation of the antioxidant transcription factor Nrf2 and elevating its downstream antioxidant genes. In addition, FGF1 △ HBS administration inhibited the activity and/or expression of hepatic lipogenic genes including SREBP-1, FAS and SCD-1. Furthermore, FGF1 △ HBS treatment rescued hepatic fatty acid oxidation signaling, including elevated expressions of CPT-1α, PPARα and PGC-1α. Moreover, FGF1 △ HBS treatment greatly increased hepatic v phosphorylation of the key energy sensor AMPK, along with upregulating its downstream genes ACC and SREBP-1 phosphorylation, indicating that FGF1 △ HBS regulation of hepatic lipid metabolism is associated with AMPK signaling pathway. Mechanistically, hepatic cells treated with palmitate (Pal) mimicked the diabetic phenotype of hepatic oxidative damage and lipid disorder seen in db/db mice, all of which could be reversed by supplementing with FGF1 △ HBS. Knockdown of Nrf2 by SiRNA completely abolished the anti-oxidative capacity of FGF1 △ HBS but did not affect the beneficial effects of FGF1 △ HBS on Pal-induced lipid metabolic disorder. Whereas, AMPK knockdown by SiRNA completely abolished FGF1 △ HBS ability to prevent Pal-induced hepatic lipotoxicity and SREBP-1-mediated lipid metabolic disorder, along with inhibiting Nrf2-mediated antioxidative signaling pathway. Most importantly, administration of FGF1 △ HBS to 9-monthold db/db mice for 3 months completely reversed the phenotype of NAFLD along with activation on Nrf2 and AMPK signaling pathways. Our findings demonstrate that, in addition to its potent glucose-lowering and insulinsensitizing effects, FGF1 ΔHBS can reverse NAFLD in T2D, by its ability to upregulate AMPK to activate Nrf2-mediated antioxidative pathway and inhibit SREBP-1-mediated lipid metabolic pathway.

show abstract

Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia

Cited by 131 publications

References 48 publications

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

High glucose and free fatty acids induce endothelial progenitor cell senescence via PGC‐1α/SIRT1 signaling pathway

A novel fibroblast growth factor 1 variant reverses nonalcoholic fatty liver disease in type 2 diabetes.

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