Wong Janica C, Fiscus Ronald R
Diabetes & Obesity Research Center, Alzheimer's & Parkinson's Disease Research Center, Cancer Research Center, Roseman Medical Education and Research Building at Summerlin Campus, Roseman University of Health Sciences, Las Vegas/Henderson, NV, U.S.A. Department of Chemistry, University of Nevada Las Vegas, Las Vegas, NV, U.S.A. Cancer Molecular Biology Section, Nevada Cancer Institute, Las Vegas, NV, U.S.A.
Diabetes & Obesity Research Center, Alzheimer's & Parkinson's Disease Research Center, Cancer Research Center, Roseman Medical Education and Research Building at Summerlin Campus, Roseman University of Health Sciences, Las Vegas/Henderson, NV, U.S.A. College of Medicine and College of Pharmacy, Roseman University of Health Sciences, Henderson, NV, U.S.A. Cancer Molecular Biology Section, Nevada Cancer Institute, Las Vegas, NV, U.S.A.
Anticancer Res. 2015 Jan;35(1):273-81.
Resveratrol increases nitric oxide (NO) production via increased expression and activation of endothelial-form-NO-synthase (eNOS) in endothelial cells. However, the role of downstream cGMP/protein kinase G (PKG) signaling, a pathway activated by NO/eNOS, in pro- and anti-angiogenic effects of resveratrol is still unclear.
Endogenous NO/cGMP/PKG pathway and downstream cell-survival proteins (Inhibitor of Apoptosis Proteins, IAPs) were studied in relation to pro- and anti-angiogenic effects of resveratrol in human umbilical vein endothelial cells (HUVECs).
Resveratrol at higher/anti-angiogenic concentrations inhibits HUVEC tube formation and cell migration/invasion (indices of angiogenesis). Resveratrol at lower concentrations stimulates proliferation and protects HUVECs against spontaneous apoptosis. 8-Br-cGMP, a direct activator of PKG, protects against pro-apoptotic effects of high-concentration resveratrol. Western blot analyses showed that anti-angiogenic concentrations of resveratrol suppress endogenous PKG kinase activity and decrease the expression of four cell-survival proteins, c-IAP1, c-IAP2, livin and XIAP.
Resveratrol-induced anti-angiogenesis/pro-apoptosis induced suppression of PKG signaling and decreased expression of the cell-survival proteins c-IAP1, c-IAP2, livin and XIAP.
白藜芦醇通过增加内皮细胞中内皮型一氧化氮合酶（eNOS）的表达和激活来提高一氧化氮（NO）的生成。然而，由NO/eNOS激活的下游环磷酸鸟苷/蛋白激酶G（PKG）信号通路在白藜芦醇的促血管生成和抗血管生成作用中的作用仍不清楚。
研究了内源性NO/cGMP/PKG信号通路及下游细胞存活蛋白（凋亡抑制蛋白，IAPs）与白藜芦醇在人脐静脉内皮细胞（HUVECs）中的促血管生成和抗血管生成作用的关系。
较高/抗血管生成浓度的白藜芦醇可抑制HUVECs的管腔形成以及细胞迁移/侵袭（血管生成指标）。较低浓度的白藜芦醇可刺激细胞增殖并保护HUVECs免受自发凋亡。PKG的直接激活剂8-溴环磷酸鸟苷可保护细胞免受高浓度白藜芦醇的促凋亡作用。蛋白质印迹分析表明，抗血管生成浓度的白藜芦醇可抑制内源性PKG激酶活性，并降低四种细胞存活蛋白c-IAP1、c-IAP2、生存素和XIAP的表达。
白藜芦醇诱导的抗血管生成/促凋亡作用可抑制PKG信号通路，并降低细胞存活蛋白c-IAP1、c-IAP2、生存素和XIAP的表达。
