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.

中文翻译：

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β-羟基丁酸酯通过促进糖尿病大鼠中VEGF的生成来拮抗主动脉内皮损伤。

内皮损伤被认为是糖尿病性血管疾病的初始病理过程，但尚未确定有效的治疗方法。尽管β-羟基丁酸酯在心血管系统中起多种保护作用，但其拮抗糖尿病内皮损伤的能力尚不清楚。据报道，β-羟基丁酸酯可引起组蛋白H3K9β-羟基丁酸酯化（H3K9bhb），从而激活基因表达；但是，尚无关于H3K9bhb在上皮血管内皮生长因子（VEGF）上调中的作用的报道，VEGF是血管内皮完整性和功能的关键因素。在此，对雄性Sprague-Dawley大鼠进行腹膜内注射链脲佐菌素诱导糖尿病，然后用不同浓度的β-羟基丁酸酯治疗。10周后，体重，血糖，检查形态变化和血清一氧化氮浓度。此外，研究了主动脉中的mRNA表达水平，蛋白含量和VEGF分布，以及总蛋白β-羟基丁酰化和H3K9bhb含量。结果显示，糖尿病大鼠主动脉内皮受到损伤，一氧化氮浓度降低，VEGF生成减少。然而，β-羟基丁酸酯治疗可减轻糖尿病对内皮的损伤并上调VEGF的产生。此外，β-羟基丁酸酯处理可导致糖尿病大鼠主动脉中明显的总蛋白β-羟基丁酰化和H3K9bhb含量显着升高。β-羟基丁酸酯预防糖尿病对主动脉内皮的伤害的能力在其中间浓度下最大。结论，