Kong Haotian, Wang Songsong, Zhang Yougang, Zhang Yangtengjiao, He Qiuxia, Dong Rong, Zheng Xiaohui, Liu Kechun, Han Liwen
School of Pharmacy and Pharmaceutical Science, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
School of Basic Medical Sciences, Shandong University, Jinan, China.
Front Pharmacol. 2022 Jun 2;13:901460. doi: 10.3389/fphar.2022.901460. eCollection 2022.
Ischemic diseases have a huge impact on people's health, which can cause blood supply blockage or restriction in specific tissues. Researchers must develop novel drugs with great efficacy and low toxicity for the prevention and treatment of such diseases. Isopropyl caffeic acid (KYZ) was one of the metabolites of caffeic acid . This study is to explore the protective effect and mechanism of KYZ on ischemic disease from the perspective of angiogenesis and , providing support for the treatment of ischemic diseases and the discovery of a new candidate drug.
The network pharmacology and molecular docking were used to predict the targets of KYZ. In addition, the effects of KYZ on damaged and normal blood vessels were evaluated using the transgenic zebrafish. The HUVECs model was used to study the effects of KYZ on proliferation, migration, and tube formation. The same dosage of caffeic acid (CA) was also administered and at the same time to assess the pharmacodynamic difference between the two compounds. Western Blot and ELISA methods were used to detect the expression of related target proteins.
The result from the network pharmacology indicated that the targets of KYZ were related to angiogenesis. It was also found that KYZ could repair the vascular damage induced by the PTK787 and promote the growth of subintestinal vessels in normal zebrafish. The result also indicated that KYZ's angiogenic ability is better than the precursor compound CA. In HUVECs, KYZ could promote cell proliferation, migration, and tube formation. Further mechanistic study suggested that the KYZ could induce the release of VEGF factor in HUVECs, up-regulate the expression of VEGFR2, and activate the PI3K/AKT and MEK/ERK signaling pathways.
These data show that KYZ may promote angiogenesis through VEGF, PI3K/AKT, and MEK/ERK signaling pathways, suggesting that KYZ exhibited great potential in the treatment of ischemic cardio-cerebrovascular diseases.
缺血性疾病对人们的健康有巨大影响，可导致特定组织的血液供应受阻或受限。研究人员必须研发出疗效显著且毒性低的新型药物用于此类疾病的预防和治疗。异丙基咖啡酸（KYZ）是咖啡酸的代谢产物之一。本研究旨在从血管生成的角度探讨KYZ对缺血性疾病的保护作用及机制，为缺血性疾病的治疗和新候选药物的发现提供支持。
采用网络药理学和分子对接技术预测KYZ的靶点。此外，利用转基因斑马鱼评估KYZ对受损血管和正常血管的影响。采用人脐静脉内皮细胞（HUVECs）模型研究KYZ对细胞增殖、迁移和管腔形成的影响。同时给予相同剂量的咖啡酸（CA）以评估两种化合物的药效学差异。采用蛋白质免疫印迹法（Western Blot）和酶联免疫吸附测定法（ELISA）检测相关靶蛋白的表达。
网络药理学结果表明，KYZ的靶点与血管生成相关。还发现KYZ可修复由PTK787诱导的血管损伤，并促进正常斑马鱼肠下血管的生长。结果还表明，KYZ的血管生成能力优于前体化合物CA。在HUVECs中，KYZ可促进细胞增殖、迁移和管腔形成。进一步的机制研究表明，KYZ可诱导HUVECs中血管内皮生长因子（VEGF）的释放，上调血管内皮生长因子受体2（VEGFR2）的表达，并激活磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）和丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK/ERK）信号通路。
这些数据表明，KYZ可能通过VEGF、PI3K/AKT和MEK/ERK信号通路促进血管生成，提示KYZ在缺血性心脑血管疾病的治疗中具有巨大潜力。
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