title: Enhancement of Lymphangiogenesis In Vitro via the Regulations of HIF-1α Expression and Nuclear Translocation by Deoxyshikonin.
abstract: The objectives of this study were to determine the effects of deoxyshikonin on lymphangiogenesis. Deoxyshikonin enhanced the ability of human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) to undergo time-dependent in vitro cord formation. Interestingly, an opposite result was observed in cells treated with shikonin. The increased cord formation ability following deoxyshikonin treatment correlated with increased VEGF-C mRNA expression to higher levels than seen for VEGF-A and VEGF-D mRNA expression. We also found that deoxyshikonin regulated cord formation of HMVEC-dLy by increasing the HIF-1 α mRNA level, HIF-1 α protein level, and the accumulation of HIF-1 α in the nucleus. Knockdown of the HIF-1 α gene by transfection with siHIF-1 α decreased VEGF-C mRNA expression and cord formation ability in HMVEC-dLy. Deoxyshikonin treatment could not recover VEGF-C mRNA expression and cord formation ability in HIF-1 α knockdown cells. This indicated that deoxyshikonin induction of VEGF-C mRNA expression and cord formation in HMVEC-dLy on Matrigel occurred mainly via HIF-1 α regulation. We also found that deoxyshikonin promoted wound healing in vitro by the induction of HMVEC-dLy migration into the wound gap. This study describes a new effect of deoxyshikonin, namely, the promotion of cord formation by human endothelial cells via the regulation of HIF-1 α . The findings suggest that deoxyshikonin may be a new drug candidate for wound healing and treatment of lymphatic diseases.
authors.affiliation: Department of Kampo Diagnostics, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan ; Department of Biopharmacy, Faculty of Pharmacy, Srinakharinwirot University, Nakhonnayok 26120, Thailand.
authors.forename: Orawin
authors.initials: O
authors.lastname: Prangsaengtong
authors.forename: Jun Yeon
authors.initials: JY
authors.lastname: Park
authors.forename: Akiko
authors.initials: A
authors.lastname: Inujima
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Shibahara
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi