A metabolite of Danshen formulae (IDHP) induces angiogenesis and protects rat brains against focal ischemia via CaMKKβ/AMPK(Thr172)/eNOS(Ser1177) signaling  

作　　者：LIAO Sha LIU Rui-min XU Dan-ni ZHU Ming-hui ZHAO Qi LUO Xian-lin LI Zhu LUO Quan-li FAN Tai-ping ZHENG Xiao-hui 

机构地区：[1]College of Life Sciences,Northwest University,Xi′an 710069,China [2]Angiogenesis and Chinese Medicine Laboratory,Department of Pharmacology,University of Cambridge,Cambridge,UK

出　　处：《中国药理学与毒理学杂志》2021年第10期734-735,共2页Chinese Journal of Pharmacology and Toxicology

基　　金：National Natural Science Foundation of China(31971143);and Primary R&D Plan of Shaanxi Province(2021KWZ-24)。

摘　　要：OBJECTIVE Only limited number of drugs are currently available for treating ischemic stroke.Therapeutic angiogenesis has recently emerged as one of the most promising therapies for cerebral ischemic injury.Isopropyl-β-(3,4-dihydroxyphenyl)-α-hydroxypropanoate(IDHP)is a metabolite derived from the botanical formulation for Dantonic®.Here,we investigated the angiogenic efficacy of IDHP in cerebral ischemia.METHODS The in vivo effects of IDHP were evaluated in the C57BL/6 mouse Matrigel plug and rat transient middle cerebral artery occlusion(tMCAO)models.Primary human umbilical vein endothelial cells(HUVEC)and human brain microvascular endothelial cells(HBMEC)were used to explore the effects of IDHP on stimulating proliferation,migration and tube formation in vitro.ELISA and Western blotting were used to quantitate the release and expression of relevant target molecules and signaling pathways.RESULTS IDHP reduced infarct volume and improved sensorimotor function in rats subjected to tMCAO by promoting angiogenesis,and promoted Matrigel neovascularization in mice.Moreover,IDHP produced a biphasic modulation on proliferation and migration both in HUVEC and HBMEC.It also induced tube formation in a 12-day HUVEC-HDF co-culture model and in Matrigel assays.IDHP-induced angiogenesis was accompanied by increased levels of p-AMPKα(Thr172)and p-eNOS(Ser1177)both in vitro and in vivo,and the decreased level of VEGF in rat brains on day 1 whereas enhanced level of VEGF on day 3 and 7 after tMCAO.Mechanistically,AMPK knockdown or pharmacologically inhibiting AMPK and its upstream kinases(CaMKKβ)inhibited the eNOS phosphorylation induced by IDHP in HUVEC.Furthermore,selective eNOS inhibitor(L-NIO),selective CaMKKβinhibitor(STO)and AMPKa inhibitor(Compound C)blocked the capillary-like tube formation in the co-culture model induced by IDHP(10 nmol·L^(-1)).CONCLUSION Collectively,these findings showed that IDHP protected rats from cerebral ischemia-reperfusion injury by promoting angiogenesis via activating CaMKKβ/AMPK(Thr1

关 键 词：ischemic stroke ANGIOGENESIS endothelial cells functional recovery 

分 类 号：R285.5[医药卫生—中药学]