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.
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.
Authors: Chong Wee Liew; Jacek Bochenski; Dan Kawamori; Jiang Hu; Colin A Leech; Krzysztof Wanic; Maciej Malecki; James H Warram; Ling Qi; Andrzej S Krolewski; Rohit N Kulkarni Journal: J Clin Invest Date: 2010-07-01 Impact factor: 14.808
Authors: S Prudente; R Baratta; F Andreozzi; E Morini; M G Farina; A Nigro; M Copetti; F Pellegrini; E Succurro; L Di Pietrantonio; C Brufani; F Barbetti; B Dallapiccola; G Sesti; V Trischitta; L Frittitta Journal: Diabetologia Date: 2010-07 Impact factor: 10.122
Authors: Jiarong Liu; Xuxia Wu; John L Franklin; Joseph L Messina; Helliner S Hill; Douglas R Moellering; R Grace Walton; Mitchell Martin; W Timothy Garvey Journal: Am J Physiol Endocrinol Metab Date: 2009-12-08 Impact factor: 4.310
Authors: H Oberkofler; A Pfeifenberger; S Soyal; T Felder; P Hahne; K Miller; F Krempler; W Patsch Journal: Diabetologia Date: 2010-05-13 Impact factor: 10.122