Inhibition of histone deacetylase 11 attenuates development of type I diabetes through reduction of oxidant stress

[Speaker] Inkyeom Kim:1
[Co-author] Hae-Ahm Lee:1
1:Pharmacology, Kyungpook National University School of Medicine, Korea

Background: Pancreas is vulnerable tissue to oxidative stress because of its lower expression level of antioxidant enzymes than other tissues. Thus, pancreas is very weak to streptozotocin (STZ) which increases reactive oxygen species (ROS) through several pathways such as damage to DNA and mitochondria, excess nitric oxide generation and xanthine oxidase.
Objective: We hypothesized that MGCD0103, a HDAC11 inhibitor, induces antioxidant enzymes such as catalase, superoxide dismutase (SOD), and glutathione reductase (GR) which results in resistance to oxidative stress in the pancreas.
Methods and Results: Change of cell morphology and viability was investigated by incucyte and MTT assay respectively. Mitochondrial membrane potential was analyzed by fluorometer after incubation with tetramethylrhodamine ethyl ester (TMRE). Intracellular ROS was measured by FACS after incubation with dichlorofluorescin diacetate (DCFDA). Expression of antioxidant enzymes was analyzed by qRT-PCR. To establish type I diabetes animal model, STZ (40 mg/kg) was injected intraperitoneally. MGCD0103 (2 mg/week) was infused with subcutaneous osmotic mini-pump for one week. STZ treatment decreased cell viability in a dose-dependent manner in several cell lines. INS-1E (beta cell origin) was the most sensitive to STZ compared with THP-1 (monocyte origin), HepG2 (liver origin), and HEK293 (kidney origin). MGCD0103 treatment protected from STZ-induced INS-1E cell death, disruption of mitochondrial membrane potential, and intracellular ROS generation. MGCD0103 increased the expression of antioxidant enzymes such as catalase (Cat), glutathione peroxidase (Gpx), glutathione reductase (GlutR), and superoxide dismutase (SOD) in INS-1E cells. STZ injection increased the blood glucose level which was inhibited by MGCD0103. STZ destroyed the structure of pancreatic islets, which was partially restored by MGCD0103 infusion. MGCD0103 infusion induced expression of SOD1, 2, and 3 in the pancreas.
Conclusion: The present study demonstrated that MGCD0103, a HDAC11 inhibitor, induces antioxidant enzymes which results in resistance to oxidative stress in the pancreas.
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