Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 176, Issue 17, Pages 3143-3160Publisher
WILEY
DOI: 10.1111/bph.14714
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Funding
- Opening Foundation of Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education
- Changjiang Scholars and Innovative Research Team in University [IRT_15R55]
- National Key Scientific Instrument and Equipment Development Project of China [2013YQ170525]
- National College Students Innovation and Entrepreneurship Training Project [201810697021]
- Scientific Research Plan Projects of Shaanxi Provincial Education Department [17JK0764]
- Primary R&D Plan of Shaanxi Province [2018SF-293, 2017KW-055]
- National Natural Science Foundation of China [81225025, 81630103]
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Background and Purpose Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic (R), a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo. Experimental Approach A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. Key Results DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. Conclusions and Implications These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.
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