Role of sirtuin-1 (SIRT1) in hypoxic injury in pancreatic β-cells

Islet transplantation (ITx) is being developed as a treatment for type 1 diabetes mellitus, but hypoxic damage to transplanted islet grafts is an important factor affecting successful transplantation. To investigate the role of sirtuin-1 (SIRT1) under hypoxic injury in INS-1 cells, one type of pancreatic β-cell lines, we used SRT1720 and GW4064 for SIRT1 activation. The small interfering RNA SIRT1 (si-SIRT1) was used to suppress SIRT1 gene expression. We measured cell viability, apoptosis, and the levels of inflammatory cytokines, including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and reactive oxygen species (ROS), under hypoxic conditions. Real-time PCR and Western blot analysis were performed. Cell viability was significantly reduced to 71% and 40% after 4 and 6 h of hypoxic conditions, respectively. Apoptosis increased significantly 2.8-fold and 5.3-fold after 4 and 6 h of hypoxia, respectively. SIRT1 expression was significantly reduced at the mRNA and protein levels during hypoxia. Hypoxic damage significantly increased the TNF-α, IL-6 and ROS levels in INS-1 cells. However, the reduced cell viability and increased inflammatory cytokines from hypoxic damage were ameliorated by SIRT1 activation in INS-1 cells. These results suggest that SIRT1 is a potential target for the protection of pancreatic β-cells against hypoxic damage during ITx.

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S1129 SRT1720 HCl SRT1720 HCl is a selective SIRT1 activator with EC50 of 0.16 μM in a cell-free assay, but is >230-fold less potent for SIRT2 and SIRT3. SRT1720 induces autophagy. (126) (6)

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