Inhibition of NADPH oxidase-related oxidative stress-triggered signaling by honokiol suppresses high glucose-induced human endothelial cell apoptosis.
Angiopathy is a major complication of diabetes. Abnormally high blood glucose is a crucial risk factor for endothelial cell damage. Nuclear factor-kappaB (NF-kappaB) has been demonstrated as a mediated signaling in hyperglycemia or oxidative stress-triggered apoptosis of endothelial cells. Here we explored the efficacy of honokiol, a small molecular weight natural product, on NADPH oxidase-related oxidative stress-mediated NF-kappaB-regulated signaling and apoptosis in human umbilical vein endothelial cells (HUVECs) under hyperglycemic conditions. The methods of morphological Hoechst staining and annexin V/propidium iodide staining were used to detect apoptosis. Submicromolar concentrations of honokiol suppressed the increases of NADPH oxidase activity, Rac-1 phosphorylation, p22(phox) protein expression, and reactive oxygen species production in high glucose (HG)-stimulated HUVECs. The degradation of IkappaBalpha and increase of NF-kappaB activity were inhibited by honokiol in HG-treated HUVECs. Moreover, honokiol (0.125-1 microM) also suppressed HG-induced cyclooxygenase (COX)-2 upregulation and prostaglandin E(2) production in HUVECs. Honokiol could reduce increased caspase-3 activity and the subsequent apoptosis and cell death triggered by HG. These results imply that inhibition of NADPH oxidase-related oxidative stress by honokiol suppresses the HG-induced NF-kappaB-regulated COX-2 upregulation, apoptosis, and cell death in HUVECs, which has the potential to be developed as a therapeutic agent to prevent hyperglycemia-induced endothelial damage.
Sheu
Meei Ling
ML
Institute of Medical Technology, National Chung Hsing University, Taiwan.
Chiang
Chih Kang
CK
Tsai
Keh Sung
KS
Ho
Feng Ming
FM
Weng
Te I
TI
Wu
Hsiao Yi
HY
Liu
Shing Hwa
SH
D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D005947:Glucose / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
D001713:Biphenyl Compounds; D051546:Cyclooxygenase 2; D005947:Glucose; D017705:Lignans; D019255:NADPH Oxidases; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D020830:rac1 GTP-Binding Protein; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C496540:PTGS2 protein, human; C086986:CYBA protein, human