β-hydroxybutyrate antagonizes aortic endothelial injury by promoting generation of VEGF in diabetic rats
β-hydroxybutyrate antagonizes aortic endothelial injury by promoting generation of VEGF in diabetic rats
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DOI：
10.1016/j.tice.2020.101345
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发表时间：
2020-06-01
期刊：
影响因子：
2.6
通讯作者：
Qi, Jinsheng
中科院分区：
文献类型：
--
作者：
Wu, Xingliang;Miao, Dazhuang;Qi, Jinsheng
内皮损伤被认为是糖尿病血管病变的初始病理过程，但目前尚无有效的治疗方法。虽然β-羟基丁酸在心血管系统中发挥各种保护作用，但其拮抗糖尿病内皮损伤的能力尚不清楚。据报道，β-羟基丁酸酯引起组蛋白H3 K9 β-羟基丁酰化（H3 K9 bhb），其激活基因表达;然而，尚未有关于H3 K9 bhb在上调血管内皮生长因子（VEGF）中的作用的报道，VEGF是内皮完整性和功能的关键因素。在这里，雄性Sprague-Dawley大鼠腹腔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周后检测体重、血糖、形态学变化及血清一氧化氮浓度。此外，还观察了VEGF在主动脉中的mRNA表达水平、蛋白含量和分布，以及总蛋白β-羟丁酰化和H3 K9 bhb含量。结果表明，糖尿病大鼠主动脉内皮损伤，沿着一氧化氮浓度降低和VEGF生成减少。然而，β-羟基丁酸酯治疗减轻了糖尿病内皮损伤，并上调了VEGF的产生。此外，β-羟基丁酸酯治疗引起显着的总蛋白β-羟基丁酰化和显着升高的H3 K9 bhb含量在主动脉中的糖尿病大鼠。β-羟基丁酸酯保护主动脉内皮免受糖尿病损伤的能力在其中等浓度下最大。总之，适度升高的β-羟基丁酸可以拮抗主动脉内皮损伤，可能是通过引起H3 K9 bhb促进糖尿病大鼠血管内皮生长因子的产生。
Endothelial injury is regarded as the initial pathological process in diabetic vascular diseases, but effective therapy has not yet been identified. Although beta-hydroxybutyrate plays various protective roles in the cardiovascular system, its ability to antagonize diabetic endothelial injury is unclear. beta-hydroxybutyrate reportedly causes histone H3K9 beta-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 beta-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 beta-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, beta-hydroxybutyrate treatment attenuated diabetic injury of the endothelium and up-regulated the generation of VEGF. Furthermore, beta-hydroxybutyrate treatment caused marked total protein beta-hydroxybutyrylation and significant elevation of H3K9bhb content in the aorta of diabetic rats. The ability of beta-hydroxybutyrate to protect against diabetic injury of the aortic endothelium was greatest for its intermediate concentration. In conclusion, moderately elevated beta-hydroxybutyrate could antagonize aortic endothelial injury, potentially by causing H3K9bhb to promote generation of VEGF in diabetic rats.