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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1355.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

TRIB3 R84 Variant Is Associated With Impaired Insulin-Mediated Nitric Oxide Production in Human Endothelial Cells

Francesco Andreozzi; Gloria Formoso; Sabrina Prudente; Marta Letizia Hribal; Assunta Pandolfi; Emanuele Bellacchio; Sara Di Silvestre; Vincenzo Trischitta; Agostino Consoli; Giorgio Sesti

From the Department of Experimental and Clinical Medicine (F.A., M.L.H., G.S.), University Magna Græcia of Catanzaro, Catanzaro, Italy; Department of Medicine and Aging Sciences (G.F., A.C.), University "G. d’Annunzio", Aging Research Center, Ce.S.I., "G. d’Annunzio" University Foundation, Chieti-Pescara, Italy; Department of Biomedical Sciences (A.P., S.D.S.), University "G. d’Annunzio", Aging Research Center, Ce.S.I., "G. d’Annunzio" University Foundation, Chieti-Pescara, Italy; Research Laboratory of Diabetes and Endocrine Disease "CSS Scientific Institute" (S.P.), San Giovanni Rotondo and "CSS-Mendel Institute", Rome, Italy; CSS-Mendel Institute (E.B.), Rome, Italy; and Department of Clinical Sciences (V.T.), "Sapienza" University, Rome, Endocrine Unit and Research Laboratory of Diabetes and Endocrine Disease "CSS Scientific Institute", San Giovanni Rotondo and "CSS-Mendel Institute", Rome, Italy.

Correspondence to Prof Agostino Consoli, MD, Department of Medicine and Aging Sciences, Edificio CeSi, room 271, University of Chieti, via dei Vestini, 1, 66100 CHIETI, Italy. E-mail consoli{at}unich.it

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.

The TRIB3 R84 variant has been associated with early age at myocardial infarction. We here report that insulin-mediated Akt activation and NO synthesis are markedly impaired in human endothelial cells carrying the variant. This finding provides a plausible biological background for the deleterious role of TRIB3 R84 on genetic susceptibility to coronary artery disease.

Key Words: insulin signaling • endothelium • nitric oxide synthase • genetics • HUVEC

Related Article:

Double Tribble: Two TRIB3 Variants, Insulin, Akt, and eNOS

Ingrid Fleming
Arterioscler Thromb Vasc Biol 2008 28: 1216-1218. [Extract] [Full Text] [PDF]

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