The Anti-Angiogenic Effect of Tryptanthrin is Mediated by the Inhibition of Apelin Promoter Activity and Shortened Mrna Half-Life in Human Vascular Endothelial Cells.

BACKGROUND:Anti-angiogenesis is an important strategy of psoriasis treatment, but the side effects of systemic agents remain difficult to overcome. Topical use of indigo naturalis ointment has been proved to improve the skin lesion of psoriasis effectively and safely and one of its major components, tryptanthrin, has been demonstrated to have anti-angiogenic effect. Apelin, which has been reported to act as an angiogenic factor that could stimulate the proliferation and migration of vascular endothelial cells and proved to be elevated in psoriasis patients, is a potential target of anti-angiogenic therapy.PURPOSE:We aim to find out if tryptanthrin works on the apelin pathway and study its anti-angiogenic mechanism.STUDY DESIGN:Human umbilical vein endothelial cells (HUVECs) were used as the in vitro model.METHODS:The effect of tryptanthrin on the expression of apelin and its receptor, APJ, was examined. The mRNA stability, promoter activity, and bioactivity of apelin, were also investigated. Migration and tube formation assay were used to evaluate the relationship between tryptanthrin and apelin. PD98059 and wortmannin were used to study the role of ERK1/2 MAPK and PI3K in apelin signaling pathway.RESULTS:We demonstrated that tryptanthrin could inhibit the expression of apelin, attenuated the stability of apelin mRNA, and significantly inhibited the apelin promoter activity. The addition of apelin-13 restored the suppression of tube formation and migration by tryptanthrin. Both PD98059 and wortmannin could down-regulate the apelin mRNA expression suggesting the important signaling role of ERK1/2 MAPK and PI3K in the gene expression of apelin.CONCLUSION:The anti-angiogenic effect of tryptanthrin was mediated by down-regulating apelin gene expression through suppression of promoter activity and decrease of mRNA stability in human vascular endothelial cells.