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Elevating CXCR7 improves angiogenic function of EPCs via Akt/GSK‐3β/Fyn‐mediated Nrf2 activation in diabetic limb ischemia
Author(s) -
Dai Xiaozhen,
Zeng Jun,
Chen Jing,
Cai Lu,
Tan Yi
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.837.1
Subject(s) - gene knockdown , progenitor cell , fyn , endothelial progenitor cell , protein kinase b , chemistry , oxidative stress , cxcr4 , endocrinology , cancer research , medicine , apoptosis , receptor , stem cell , microbiology and biotechnology , biology , proto oncogene tyrosine protein kinase src , biochemistry , chemokine
Rational 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) and high glucose (HG) also reduced CXCR7 expression, impaired tube formation and increased oxidative stress and apoptosis. The damaging effects of ox‐LDL and 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 and HG inhibited Akt and GSK‐3β phosphorylation, nuclear export of Fyn and nuclear localization of Nrf2, resulting in inhibiting Nrf2 downstream target genes HO‐1, NQO‐1 and catalase, and a corresponding increase in EPC oxidative stress. This destructive cascade could be 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 for treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by the Akt/GSK‐3β/Fyn pathway producing increased activity of Nrf2. Support or Funding Information This study was supported in part by a Junior Faculty Award (1–13‐JF‐53) from American Diabetes Association, an Innovative Grant (1‐INO‐2014‐122‐A‐N) from Juvenile Diabetes Research Foundation, NSFC projects (81573435, 81200917, 81200239, 81370917).