TY - JOUR
T1 - Soluble CD40 ligand induces endothelial dysfunction in human and porcine coronary artery endothelial cells
AU - Chen, Changyi
AU - Chai, Hong
AU - Wang, Xinwen
AU - Jiang, Jun
AU - Jamaluddin, Md Sana
AU - Liao, Dan
AU - Zhang, Yuqing
AU - Wang, Hao
AU - Bharadwaj, Uddalak
AU - Zhang, Sheng
AU - Li, Min
AU - Lin, Peter
AU - Yao, Qizhi
PY - 2008/10/15
Y1 - 2008/10/15
N2 - The purpose of this study was to determine the effects and mechanisms of sCD40L on endothelial dysfunction in both human coronary artery endothelial cells (HCAECs) and porcine coronary artery rings. HCAECs treated with sCD40L showed significant reductions of endothelial nitric oxide synthase (eNOS) mRNA and protein levels, eNOS mRNA stability, eNOS enzyme activity, and cellular NO levels, whereas superoxide anion (o2-) production was significantly increased. sCD40L enhanced eNOS mRNA 3'UTR binding to cytoplasmic molecules and induced a unique expression pattern of 95 microRNAs. sCD40L significantly decreased mitochondrial membrane potential, and catalase and SOD activities, whereas it increased NADPH oxidase (NOX) activity. sCD40L increased phosphorylation of MAPKs p38 and ERK1/2 as well as IκBα and enhanced NF-κB nuclear translocation. In porcine coronary arteries, sCD40L significantly decreased endothelium-dependent vasorelaxation and eNOS mRNA levels, whereas it increased O2- levels. Antioxidant seleno-L-methionine; chemical inhibitors of p38, ERK1/2, and mitochondrial complex II; as well as dominant negative mutant forms of IκBα and NOX4 effectively blocked sCD40L-induced eNOS down-regulation in HCAECs. Thus, sCD40L reduces eNOS levels, whereas it increases oxidative stress through the unique molecular mechanisms involving eNOS mRNA stability, 3'UTR-binding molecules, micro-RNAs, mitochondrial function, ROS-related enzymes, p38, ERK1/2, and NF-κB signal pathways in endothelial cells.
AB - The purpose of this study was to determine the effects and mechanisms of sCD40L on endothelial dysfunction in both human coronary artery endothelial cells (HCAECs) and porcine coronary artery rings. HCAECs treated with sCD40L showed significant reductions of endothelial nitric oxide synthase (eNOS) mRNA and protein levels, eNOS mRNA stability, eNOS enzyme activity, and cellular NO levels, whereas superoxide anion (o2-) production was significantly increased. sCD40L enhanced eNOS mRNA 3'UTR binding to cytoplasmic molecules and induced a unique expression pattern of 95 microRNAs. sCD40L significantly decreased mitochondrial membrane potential, and catalase and SOD activities, whereas it increased NADPH oxidase (NOX) activity. sCD40L increased phosphorylation of MAPKs p38 and ERK1/2 as well as IκBα and enhanced NF-κB nuclear translocation. In porcine coronary arteries, sCD40L significantly decreased endothelium-dependent vasorelaxation and eNOS mRNA levels, whereas it increased O2- levels. Antioxidant seleno-L-methionine; chemical inhibitors of p38, ERK1/2, and mitochondrial complex II; as well as dominant negative mutant forms of IκBα and NOX4 effectively blocked sCD40L-induced eNOS down-regulation in HCAECs. Thus, sCD40L reduces eNOS levels, whereas it increases oxidative stress through the unique molecular mechanisms involving eNOS mRNA stability, 3'UTR-binding molecules, micro-RNAs, mitochondrial function, ROS-related enzymes, p38, ERK1/2, and NF-κB signal pathways in endothelial cells.
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U2 - 10.1182/blood-2008-03-143479
DO - 10.1182/blood-2008-03-143479
M3 - Article
C2 - 18658029
AN - SCOPUS:54049156519
SN - 0006-4971
VL - 112
SP - 3205
EP - 3216
JO - Blood
JF - Blood
IS - 8
ER -