Effects of hypocrellin A on expression of vascular endothelial growth factor and endothelin-1 in human umbilical endothelial cells.
Increased endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) and activation of protein kinase C (PKC) are co-contributors to endothelial hyperpermeability in diabetes. Several lines of evidence have suggested a hypothesis that activation of specific PKC isoforms are the causative factor in ET-1 and VEGF mediated endothelial dysfunction. In the present study, we tested this hypothesis with hypocrellin A, a naturally occurring PKC inhibitor from a Chinese plant. Human umbilical vein endothelial cells (HUVECs) were incubated with 20 mM glucose in both the presence and absence of hypocrellin A, after which, the protein expression and release of VEGF and mRNA expression and release of ET-1 were measured. VEGF and ET-1 were released into the medium and expressions of VEGF protein and ET-1 mRNA were significantly increased in HUVECs incubated with 20 mM glucose. Hypocrellin A (150 nM) significantly decreased VEGF release (117 +/- 3 vs. 180 +/- 11 pg/mg, p < 0.05) and VEGF protein expression (from 130 +/- 14% to 88 +/- 18.5%, p < 0.05). ET-1 release was also reduced in hypocrellin A treated HUVECs (63.3 +/- 9.9 vs. 75.2 +/- 12.6 ng/mg). Hypocrellin A significantly reversed the effect of high glucose on ET-1 mRNA expression (p < 0.05). The results revealed that PKC activation plays a pivotal role in VEGF and ET-1 mediated endothelial permeability. The naturally occurring compound hypocrellin A may be a potentially novel treatment for endothelial dysfunction in diabetes.
Dang
Lei
L
Department of Medical Molecular and BioSciences, University of Technology Sydney, Sydney, New South Wales, Australia.
Seale
J Paul
JP
Qu
Xianqin
X
D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006999:Hypocreales; D008353:Mannitol / Q000494:pharmacology; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D019800:Phenol; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011809:Quinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D014470:Umbilical Cord / Q000098:blood supply; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism*
D004365:Drugs, Chinese Herbal; D019332:Endothelin-1; D011809:Quinones; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D019800:Phenol; D008353:Mannitol; D010569:Perylene; D011493:Protein Kinase C; D005947:Glucose; C048388:hypocrellin A