β-hydroxybutyrate antagonizes aortic endothelial injury by promoting generation of VEGF in diabetic rats

Endothelial injury is regarded as the initial pathological process in diabetic vascular diseases, but effective therapy has not yet been identified. Although β-hydroxybutyrate plays various protective roles in the cardiovascular system, its ability to antagonize diabetic endothelial injury is unclear. β-hydroxybutyrate reportedly causes histone H3K9 β-hydroxybutyrylation (H3K9bhb), which activates gene expression; however, there has been no report regarding the role of H3K9bhb in up-regulation of vascular endothelial growth factor (VEGF), a crucial factor in endothelial integrity and function. Here, male Sprague-Dawley rats were intraperitoneally injected with streptozotocin to induce diabetes, and then treated with different concentrations of β-hydroxybutyrate. After 10 weeks, body weight, blood glucose, morphological changes and serum nitric oxide concentration were examined. Moreover, the mRNA expression level, protein content and distribution of VEGF in the aorta were investigated, as were total protein β-hydroxybutyrylation and H3K9bhb contents. The results showed injury of aortic endothelium, along with reductions of the concentration of nitric oxide and generation of VEGF in diabetic rats. However, β-hydroxybutyrate treatment attenuated diabetic injury of the endothelium and up-regulated the generation of VEGF. Furthermore, β-hydroxybutyrate treatment caused marked total protein β-hydroxybutyrylation and significant elevation of H3K9bhb content in the aorta of diabetic rats. The ability of β-hydroxybutyrate to protect against diabetic injury of the aortic endothelium was greatest for its intermediate concentration. In conclusion, moderately elevated β-hydroxybutyrate could antagonize aortic endothelial injury, potentially by causing H3K9bhb to promote generation of VEGF in diabetic rats.