TY - JOUR
T1 - TRIB3 R84 variant is associated with impaired insulin-mediated nitric oxide production in human endothelial cells
AU - Andreozzi, Francesco
AU - Formoso, Gloria
AU - Prudente, Sabrina
AU - Hribal, Marta Letizia
AU - Pandolfi, Assunta
AU - Bellacchio, Emanuele
AU - Silvestre, Sara Di
AU - Trischitta, Vincenzo
AU - Consoli, Agostino
AU - Sesti, Giorgio
PY - 2008/7/1
Y1 - 2008/7/1
N2 - Background - In the endothelium, insulin promotes nitric oxide (NO) production, through the insulin receptor/IRS-1/PI3-Kinase/Akt/eNOS signaling pathway. An inhibitor of insulin action, TRIB3, has recently been identified which affects insulin action by binding to and inhibiting Akt phosphorylation. We have recently described a Q84R gain-of-function polymorphism of TRIB3 with the R84 variant being associated with insulin resistance and an earlier age at myocardial infarction. Methods and Results - To investigate the TRIB3 R84 variant impact on endothelial insulin action, we cultured human umbilical vein endothelial cells (HUVECs) naturally carrying different TRIB3 genotypes (QQ-, QR-, or RR-HUVECs). TRIB3 inhibitory activity on insulin-stimulated Akt phosphorylation and the amount of protein which was coimmunoprecipitable with Akt were significantly greater in QR- and RR- as compared to QQ- HUVECs. After insulin stimulation, Akt and eNOS activation as well as NO production were markedly decreased in QR- and RR- as compared to QQ-HUVECs. TRIB3 molecular modeling analysis provided insights into the structural changes related to the polymorphisms potentially determining differences in protein-protein interaction with Akt. Conclusions - Our data demonstrate that the TRIB3 R84 variant impairs insulin signaling and NO production in human endothelial cells. This finding provides a plausible biological background for the deleterious role of TRIB3 R84 on genetic susceptibility to coronary artery disease.
AB - Background - In the endothelium, insulin promotes nitric oxide (NO) production, through the insulin receptor/IRS-1/PI3-Kinase/Akt/eNOS signaling pathway. An inhibitor of insulin action, TRIB3, has recently been identified which affects insulin action by binding to and inhibiting Akt phosphorylation. We have recently described a Q84R gain-of-function polymorphism of TRIB3 with the R84 variant being associated with insulin resistance and an earlier age at myocardial infarction. Methods and Results - To investigate the TRIB3 R84 variant impact on endothelial insulin action, we cultured human umbilical vein endothelial cells (HUVECs) naturally carrying different TRIB3 genotypes (QQ-, QR-, or RR-HUVECs). TRIB3 inhibitory activity on insulin-stimulated Akt phosphorylation and the amount of protein which was coimmunoprecipitable with Akt were significantly greater in QR- and RR- as compared to QQ- HUVECs. After insulin stimulation, Akt and eNOS activation as well as NO production were markedly decreased in QR- and RR- as compared to QQ-HUVECs. TRIB3 molecular modeling analysis provided insights into the structural changes related to the polymorphisms potentially determining differences in protein-protein interaction with Akt. Conclusions - Our data demonstrate that the TRIB3 R84 variant impairs insulin signaling and NO production in human endothelial cells. This finding provides a plausible biological background for the deleterious role of TRIB3 R84 on genetic susceptibility to coronary artery disease.
KW - Endothelium
KW - Genetics
KW - HUVEC
KW - Insulin signaling
KW - Nitric oxide synthase
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U2 - 10.1161/ATVBAHA.108.162883
DO - 10.1161/ATVBAHA.108.162883
M3 - Article
C2 - 18436806
AN - SCOPUS:46249084940
VL - 28
SP - 1355
EP - 1360
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 7
ER -