Abstract 388: TXNIP Knockdown Rescues Diabetes-Related Impairment in Endothelial Progenitor Cell-Mediated Angiogenesis
Introduction: Endothelial progenitor cell (EPC) participation in neovascularization of ischemic tissue is impaired in diabetes mellitus. Thioredoxin interacting protein (TXNIP) is strongly induced by glucose. TXNIP is overexpressed in tissues of diabetes sufferers and is associated with impaired angiogenesis. We hypothesized that gene-silencing of TXNIP in diabetic EPC would ameliorate impaired EPC angiogenic function.
Methods and results: EPC (CD34+/CD45+/KDR+) isolated from young Type 1 diabetes patients were markedly reduced, which was associated with induction of TXNIP and reduced expression of VEGF compared to age- and sex-matched healthy controls. We further found that high glucose (15-25 mmol/L) impaired EPC angiogenic processes in vitro, including cell proliferation, migration and vascular network formation. This was associated with induction of TXNIP and a reduction in VEGF. However, EPC transfected with siRNA to TXNIP were protected from high-glucose mediated impairment of angiogenic processes and had normal VEGF production. Next, diabetic and healthy EPC were treated with TXNIP siRNA and xenotransplanted into a normoglycemic Balb/c nude mouse model of unilateral hindlimb ischemia. Xenotransplanted diabetic EPC were associated with reductions in blood flow recovery (laser Doppler perfusion imaging) and increased tissue ischemia/amputations. However, gene silencing of TXNIP in diabetic EPC restored blood flow recovery, with reductions in tissue ischemia/amputations, to levels seen in mice xenotransplanted with healthy control EPC.
Conclusion: Hyperglycemia-mediated induction of TXNIP impairs EPC angiogenic function in vitro and in vivo. Inhibition of TXNIP in diabetic EPC rescues impaired angiogenesis, with implications for therapeutic modulation of diabetic vascular disease.
- © 2012 by American Heart Association, Inc.