Vascular Protection of TPE-CA on Hyperhomocysteinemia-induced Vascular Endothelial Dysfunction through AA Metabolism Modulated CYPs Pathway
Vascular Protection of TPE-CA on Hyperhomocysteinemia-induced Vascular Endothelial Dysfunction through AA Metabolism Modulated CYPs Pathway
复制标题
TPE-CA 通过 AA 代谢调节 CYP 途径对高同型半胱氨酸血症诱导的血管内皮功能障碍进行血管保护
DOI：
10.7150/ijbs.35245
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Liu, Yuanyan
中科院分区：
文献类型：
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作者：
Li, Hui;Liu, Zhenli;Liu, Yuanyan
血浆中高浓度的同型半胱氨酸（homocysteine，Hcy）可导致血管内皮功能障碍，并可能最终加速心血管疾病（cardiovascular diseases，CVD）的发展。虽然临床上已有多种B族维生素用于治疗高同型半胱氨酸血症（HHcy），但由于其治疗机制有限，疗效不理想。因此，为提高疗效，开发新的有效治疗策略应提上日程。枳实总酚提取物。（TPE-CA）是一种天然酚类化合物，主要含有黄酮、黄烷酮及其糖基衍生物、黄酮醇、多甲氧基黄酮和香豆素。以往的研究表明，生物活性酚类化合物具有较强的血管保护作用，被认为是一种抗心血管疾病的保护剂。TPE-CA抑制高同型半胱氨酸的确切机制有助于揭示其对心血管疾病的治疗作用。在此，TPE-CA对HHcy诱导的血管内皮功能障碍的多靶点协同机制以推断的方式被揭示。TPE-CA处理的效果明显优于B族维生素处理。网络药理学被用来确定化合物之间的相互关系，潜在的目标和推定的途径。进一步的实验验证表明，TPE-CA治疗HHcy不仅可以通过上调Hcy代谢中的转硫途径有效降低血浆Hcy水平，还可以通过激活花生四烯酸（AA）代谢中的细胞色素P450酶（CYPs）环氧合酶信号级联和抑制CYPs羟化酶信号级联来恢复HHcy诱导的血管内皮功能障碍。
A high concentration of homocysteine (Hcy) in plasma induces vascular endothelial dysfunction, and it may ultimately accelerate the development of cardiovascular diseases (CVDs). Although several B vitamins have been clinically applied for hyperhomocysteinemia (HHcy) treatment, the outcomes are not satisfied due to their limited therapeutic mechanism. Hence, in order to improve the curative effect, development of new effective therapeutic strategies should be put on the agenda. Total phenolic extracts of Citrus aurantium L. (TPE-CA) is a naturally obtained phenolic mixture, mainly containing flavones, flavanones and their glycosyl derivatives, flavonols, polymethoxyflavones and coumarins. Previous reports indicated that bioactive phenolic compounds possessed potent vascular protective effects and regarded as a protective agent against CVDs. Intriguingly, the exact mechanism underlying the suppressed effects of TPE-CA on HHcy could assist in revealing their therapy on CVDs. Here, the multi-targeted synergistic mechanism of TPE-CA on HHcy-induced vascular endothelial dysfunction was uncovered in a deduced manner. TPE-CA treatment exhibited an obvious superiority than that of B vitamins treatment. Network pharmacology was employed to identify the interrelationships among compounds, potential targets and putative pathways. Further experimental validation suggested that the treatment of TPE-CA for HHcy could not only effectively reduce the Hcy level in plasma through up-regulating transsulfuration pathway in Hcy metabolism, but also restore the HHcy-induced vascular endothelial dysfunction by activating cytochrome P450 enzymes (CYPs) epoxygenase signal cascades and inhibiting CYPs hydroxylase signal cascades in arachidonic acid (AA) metabolism.