AGEs Decreased SIRT3 Expression and SIRT3 Activation Protected AGEs-Induced EPCs’ Dysfunction and Strengthened Anti-oxidant Capacity

Abstract

Advanced glycation end products (AGEs) have been confirmed to induce dysfunction in endothelial progenitor cells (EPCs) and play key roles in pathogenesis of diabetes-related vascular complications. The major function of sirtuin 3 (SIRT3) is to orchestrate oxidative metabolism and control reactive oxygen species (ROS) homeostasis, which are more closely related to EPCs' dysfunction. Our study therefore was designed to explore the role of SIRT3 on AGEs-induced EPCs dysfunction of. EPCs isolated from healthy adults were stimulated with AGEs and the expression of SIRT3 was assessed. Then, EPCs transfected with ad-SIRT3 or siRNA-SIRT3 were cultured with or without AGEs. EPCs function, including proliferation, migration; expression of manganese superoxide dismutase (MnSOD), ROS production, and interleukin-8 (IL-8); and vascular endothelial growth factor (VEGF) production were measured. In some experiments, EPCs were pre-cultured with anti-receptor for advanced glycation end products (RAGE) antibody or anti-neutralizing antibody, and then proliferation, migration, expression of MnSOD, ROS production, and IL-8 and VEGF production were measured. Our results showed that SIRT3 expressed in EPCs and AGEs decreased SIRT3 expression. SIRT3 knockdown with siRNA-SIRT3 promoted dysfunction in EPCs whereas SIRT3 activation with ad-SIRT3 strengthened anti-oxidant capacity and protected AGE-impaired dysfunction. Moreover, RAGE may involve in AGEs-decreased SIRT3 expression in EPCs. These data suggested an important role of SIRT3 in regulating EPCs bioactivity.

1,3,6,7‐Tetrahydroxy‐8‐prenylxanthone ameliorates inflammatory responses resulting from the paracrine interaction of adipocytes and macrophages

“…A deficiency in SIRT3 and the accompanying mitochondrial protein hyperacetylation were reported to be associated with the development of metabolic syndrome and hepatocyte injury (Chang et al, ; Liu et al, ). RAW264.7 macrophages with SIRT3 knockdown expressed higher iNOS protein and transcript levels of inflammatory cytokines, which led to an elevated inflammatory state (Xu et al, ).…”

Emerging Evidence of Epigenetic Modifications in Vascular Complication of Diabetes

“…AGEs have been recently reported to decrease SIRT3 levels and SIRT3 knock down was associated with endothelial dysfunction in endothelial progenitor cells (EPCs). Moreover, SIRT3 augmentation ameliorated cellular dysfunction and enhanced antioxidant machinery ( 31 ). SIRT6 deficiency has been found to impair wound healing in diabetic db/db mice and induce pro-inflammatory cytokines and oxidative stress, and decrease angiogenesis, suggesting its potential role in diabetic vasculopathy ( 32 ).…”

The Impact of Advanced Glycation End-Products (AGEs) on Proliferation and Apoptosis of Primary Stem Cells: A Systematic Review

“…In addition, endothelial progenitor cells (EPCs), a specific type of PBMCs, were investigated [1]. Isolation of EPCs from blood samples was performed by gradient density centrifugation [35][36][37][38][39][40][41][42][43] (Table 1). Regarding the origin of blood, one study isolated EPCs from umbilical cord blood [37] while in all other studies peripheral blood was used [35,36,[38][39][40][41][42][43][44].…”