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

Abstract

Rationale Endothelial progenitor cells (EPCs) respond to SDF-1 through receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes induced EPCs dysfunction remains unknown. Objective To determine the role of SDF-1 receptors in diabetic EPCs dysfunction. Methods and Results CXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, while up-regulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein (ox-LDL) or high glucose (HG) also reduced CXCR7 expression, impaired tube formation and increased oxidative stress and apoptosis. The damaging effects of ox-LDL or HG were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus (CXCR7-EPCs) but not in EPCs transduced with control lentivirus (Null-EPCs). Most importantly, CXCR7-EPCs were superior to Null-EPCs for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that ox-LDL or HG inhibited Akt and GSK-3β phosphorylation, nuclear export of Fyn and nuclear localization of Nrf2, blunting Nrf2 downstream target genes HO-1, NQO-1 and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in CXCR7-EPCs. Furthermore, inhibition of PI3K/Akt prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo. Conclusions Elevated expression of CXCR7 enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by an Akt/GSK-3β/Fyn pathway via increased activity of Nrf2.

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

“…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.…”

“…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].…”

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

“…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).…”

“…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).…”

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

“…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) .…”