HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetes-induced liver damage and FGF21 synthesis and secretion leading to aortic protection.

Abstract

Vascular complications are common pathologies associated with type 1 diabetes. In recent years, histone deacetylation enzyme (HDAC) inhibitors have been shown to be successful in preventing atherosclerosis. To investigate the mechanism for HDAC3 inhibition in preventing diabetic aortic pathologies, male OVE26 type 1 diabetic mice and age-matched wild-type (FVB) mice were given the HDAC3-specific inhibitor RGFP-966 or vehicle for 3 mo. These mice were then euthanized immediately or maintained for an additional 3 mo without treatment. Levels of aortic inflammation and fibrosis and plasma and fibroblast growth factor 21 (FGF21) levels were determined. Because the liver is the major organ for FGF21 synthesis in diabetic animals, the effects of HDAC3 inhibition on hepatic FGF21 synthesis were examined. Additionally, hepatic miR-200a and kelch-like ECH-associated protein 1 (Keap1) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation were measured. HDAC3 inhibition significantly reduced aortic fibrosis and inflammation in OVE26 mice at both 3 and 6 mo. Plasma FGF21 levels were significantly higher in RGFP-966-treated OVE26 mice compared with vehicle-treated mice at both time points. It also significantly reduced hepatic pathologies associated with diabetes, accompanied by increased FGF21 mRNA and protein expression. HDAC3 inhibition also increased miR-200a expression, reduced Keap1 protein levels, and increased Nrf2 nuclear translocation with an upregulation of antioxidant gene and FGF21 transcription. Our results support a model where HDAC3 inhibition may promote Nrf2 activity by increasing miR-200a expression with a concomitant decrease in Keap1 to preserve hepatic FGF21 synthesis. The preservation of hepatic FGF21 synthesis ultimately leads to a reduction in diabetes-induced aorta pathologies.

• Authors: Jian Zhang, Zheng Xu, Junlian Gu, Saizhi Jiang, Quan Liu, Yang Zheng, Jonathan H Freedman, Jian Sun, Lu Cai
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 315 Issue 2 Pg. E150-E162 (08 01 2018) ISSN: 1522-1555 [Electronic] United States
• PMID: 29634312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Histone Deacetylase Inhibitors
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• MicroRNAs
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• fibroblast growth factor 21
• Fibroblast Growth Factors
• Histone Deacetylases
• histone deacetylase 3

Topics

• Animals
• Aorta (drug effects)
• Cardiotonic Agents (pharmacology)
• Diabetes Complications (prevention & control)
• Diabetes Mellitus, Type 1 (metabolism)
• Fibroblast Growth Factors (biosynthesis)
• Fibrosis (pathology, prevention & control)
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (drug effects)
• Inflammation (pathology, prevention & control)
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• Liver Diseases (etiology, pathology, prevention & control)
• Male
• Mice
• MicroRNAs (metabolism)
• NF-E2-Related Factor 2 (metabolism)