title: Dammarenediol-II Prevents VEGF-Mediated Microvascular Permeability in Diabetic Mice.
abstract: Diabetic retinopathy is a major diabetic complication predominantly caused by vascular endothelial growth factor (VEGF)-induced vascular permeability in the retina; however, treatments targeting glycemic control have not been successful. Here, we investigated the protective effect of dammarenediol-II, a precursor of triterpenoid saponin biosynthesis, on VEGF-induced vascular leakage using human umbilical vein endothelial cells (HUVECs) and diabetic mice. We overproduced the compound in transgenic tobacco expressing Panax ginseng dammarenediol-II synthase gene and purified using column chromatography. Analysis of the purified compound using a gas chromatography-mass spectrometry system revealed identical retention time and fragmentation pattern to those of authentic standard dammarenediol-II. Dammarenediol-II inhibited VEGF-induced intracellular reactive oxygen species generation, but it had no effect on the levels of intracellular Ca(2+) in HUVECs. We also found that dammarenediol-II inhibited VEGF-induced stress fiber formation and vascular endothelial-cadherin disruption, both of which play critical roles in modulating endothelial permeability. Notably, microvascular leakage in the retina of diabetic mice was successfully inhibited by intravitreal dammarenediol-II injection. Our results suggest that the natural drug dammarenediol-II may have the ability to prevent diabetic microvascular complications, including diabetic retinopathy.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Su-Hyeon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Se-Hui
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Yeon-Ju
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Forest Resources, College of Forest and Environmental Sciences, Kangwon National University, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Han
authors.affiliation: Department of Forest Resources, College of Forest and Environmental Sciences, Kangwon National University, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Yong-Eui
authors.initials: YE
authors.lastname: Choi
authors.affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Hae-Deun
authors.initials: HD
authors.lastname: Hong
authors.affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Hye-Yoon
authors.initials: HY
authors.lastname: Jeon
authors.affiliation: Department of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea.
authors.forename: JongYun
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, Korea.
authors.forename: SungHun
authors.initials: S
authors.lastname: Na
authors.affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-Do, 200-701, Korea.
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D008401:Gas Chromatography-Mass Spectrometry; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D030821:Plants, Genetically Modified / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000503:physiopathology; D012503:Saponins / Q000096:biosynthesis / Q000494:pharmacology*; D014026:Nicotiana / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D012503:Saponins; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; C106188:dammarenediol; D019883:Alkyl and Aryl Transferases; C514651:dammarenediol-II synthase, Panax ginseng; D002118:Calcium
keywords: ROS generation; dammarenediol-II; diabetic retinopathy; microvascular leakage; vascular endothelial growth factor