Anti-angiogenic effect of tetraacetyl-phytosphingosine.
In a search for the wound healing accelerators, we found that tetraacetyl-phytosphingosine (TAPS), a sphingolipid metabolite produced by phytosphingosine acetylation, has significant inhibitory potential on healing of rabbit ear wound. As angiogenesis is fundamental to proper wound healing, we examined the effect of TAPS on angiogenesis using human umbilical vein endothelial cells cultured in vitro. TAPS markedly decreased vascular endothelial growth factor (VEGF)-induced chemotactic migration and capillary-like tube formation. Recognizing its inhibitory potential on angiogenesis, we further investigated the action mechanism of TAPS. TAPS significantly inhibited VEGF-induced proteolytic enzyme production, including matrix metalloproteinase-2, urokinase-type plasminogen activator and plasminogen activator inhibitor-1. TAPS also suppressed VEGF-induced phosphorylation of p42/44 extracellular signal-regulated kinase and c-Jun N-terminal kinase. In addition, TAPS abolished VEGF-induced intracellular calcium increase, measured using laser scanning confocal microscopy. Together, these results suggest that TAPS exerts its inhibitory action on angiogenesis through the inhibition of mitogen-activated protein kinase activation and intracellular calcium increase, thereby affecting the process of wound healing negatively.
Kwon
Yoo Bin
YB
Department of Dermatology and Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, Korea.
Kim
Chang Deok
CD
Kim
Bo Joong
BJ
Kim
Min-Young
MY
Park
Chang Seo
CS
Yoon
Tae-Jin
TJ
Seo
Young-Joon
YJ
Suhr
Ki-Beom
KB
Park
Jang-Kyu
JK
Lee
Jeung-Hoon
JH
D000107:Acetylation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects*
D017395:Plasminogen Activator Inhibitor 1; D042461:Vascular Endothelial Growth Factor A; C520613:tetraacetyl-phytosphingosine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; C012491:phytosphingosine; D013110:Sphingosine; D002118:Calcium