Janica C Wong1, Ronald R Fiscus2. 1. 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. 2. 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. rfiscus@roseman.edu.
Abstract
BACKGROUND: 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. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSION: 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. Copyright
BACKGROUND: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. MATERIALS AND METHODS: 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). RESULTS: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. CONCLUSION: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. Copyright