He Shuang, Chen Rongrong, Peng Li, Jiang Zhenzuo, Liu Haixin, Chen Zihao, Zhao Tiechan, Orgah John Owoicho, Ren Jie, Zhang Peng, Wang Yuefei, Gao Xiumei, Zhu Yan
State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.
Research and Development Center of Traditional Chinese Medicine, Tianjin International Joint Academy of Biomedicine, TEDA, 220 Dongting Road, Tianjin, 300457, China.
Chin Med. 2022 Jan 4;17(1):4. doi: 10.1186/s13020-021-00557-5.
We investigate the chemical basis and mechanism of angiogenesis regulation by a multicomponent Chinese medicine Danhong injection (DHI).
DHI was fractionated and screened for angiogenesis activities by in vitro tube formation and migration assays. The composition of DHI components was determined by UPLC. The effects of the main active monomers on angiogenesis-related gene and protein expression in endothelial cells were determined by qPCR and Western blotting analyses. Mouse hind limb ischemia and tumor implant models were used to verify the angiogenesis effects in vivo by Laser Doppler and bioluminescent imaging, respectively.
Two distinct chemical components, one promoting (pro-angiogenic, PAC) and the other inhibiting (anti-angiogenic, AAC) angiogenesis, were identified in DHI. PAC enhanced angiogenesis and improved recovery of ischemic limb perfusion while AAC reduced Lewis lung carcinoma growth in vivo in VEGFR-2-Luc mice. Among the PAC or AAC monomers, caffeic acid and rosmarinic acid upregulated TSP1 expression and downregulated KDR and PECAM expression. Caffeic acid and rosmarinic acid significantly decreased while protocatechuic aldehyde increased CXCR4 expression, which are consistent with their differential effects on EC migration.
DHI is capable of bi-directional regulation of angiogenesis in disease-specific manner. The pro-angiogenesis activity of DHI promotes the repair of ischemic vascular injury, whereas the anti-angiogenesis activity inhibits tumor growth. The active pro- and anti-angiogenesis activities are composed of unique chemical combinations that differentially regulate angiogenesis-related gene networks.
我们研究了多成分中药丹红注射液（DHI）调节血管生成的化学基础和机制。
通过体外管形成和迁移试验对DHI进行分级分离并筛选其血管生成活性。采用超高效液相色谱法测定DHI成分的组成。通过定量聚合酶链反应（qPCR）和蛋白质免疫印迹分析确定主要活性单体对内皮细胞中血管生成相关基因和蛋白质表达的影响。分别使用小鼠后肢缺血和肿瘤植入模型，通过激光多普勒和生物发光成像在体内验证血管生成作用。
在DHI中鉴定出两种不同的化学成分，一种促进血管生成（促血管生成成分，PAC），另一种抑制血管生成（抗血管生成成分，AAC）。PAC增强血管生成并改善缺血肢体灌注的恢复，而AAC在VEGFR-2-Luc小鼠体内降低Lewis肺癌的生长。在PAC或AAC单体中，咖啡酸和迷迭香酸上调TSP1表达，下调KDR和PECAM表达。咖啡酸和迷迭香酸显著降低而原儿茶醛增加CXCR4表达，这与其对内皮细胞迁移的不同作用一致。
DHI能够以疾病特异性方式对血管生成进行双向调节。DHI的促血管生成活性促进缺血性血管损伤的修复，而抗血管生成活性抑制肿瘤生长。促血管生成和抗血管生成的活性由独特的化学组合组成，这些组合以不同方式调节血管生成相关基因网络。
