The TRIB3 R84 variant is associated with increased carotid intimamedia thickness in vivo and with enhanced MAPK signalling in human endothelial cells

Gloria Formoso, Pamela Di Tomo, Francesco Andreozzi, Elena Succurro, Sara Di Silvestre, Sabrina Prudente, Francesco Perticone, Vincenzo Trischitta, Giorgio Sesti, Assunta Pandolfi, Agostino Consoli

Research output: Contribution to journalArticlepeer-review

Abstract

Aims TRIB3, a mammalian tribbles homologue, affects insulin signalling and action by inhibiting Akt phosphorylation. A TRIB3 Q84R gain-of-function polymorphism has been associated with insulin resistance both in vitro and in vivo and with several atherosclerotic phenotypes, including increased carotid intimamedia thickness (IMT). We wanted to replicate this latter association and, if so, to get deeper insights about the molecular mechanisms underlying the role of the TRIB3 Q84R polymorphism in atherosclerosis.Methods and results In 430 Caucasians of European ancestry, carotid IMT was increased in QR (n 116) and RR (n 15) when compared with QQ (n 299) subjects (P 0.009), thus replicating similar data recently obtained among Asians. In human umbilical vein endothelial cells (HUVECs) naturally carrying the QQ genotype, 24 h insulin stimulation increased monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, and mitogen-activated protein kinase (MAPK) kinase (MEK)MAPK activation. Conversely, QR- and RR-HUVECs had increased unstimulated monocyte adhesion, VCAM-1 and ICAM-1 expression, and MEKMAPK activation which did not increase further upon insulin stimulation. In addition, QQ-, QR-, and RR-HUVECs showed similar basal Akt phosphorylation and nitric oxide synthase activity which, however, were significantly increased by insulin only in QQ cells. Conclusion The TRIB3 R4 variant is associated with increased carotid IMT also in Caucasians, thus replicating previous data obtained in Asians. In addition, in HUVECs, this variant is associated with unbalanced insulin signalling. This abnormality may favour vasoreactivity, intimamedia thickening, and plaque formation and may, therefore, underlie the deleterious role exerted by the variant on the susceptibility to atherosclerosis.

Original languageEnglish
Pages (from-to)184-192
Number of pages9
JournalCardiovascular Research
Volume89
Issue number1
DOIs
Publication statusPublished - Jan 1 2011

Keywords

  • Atherosclerosis
  • Cardiovascular diseases
  • Endothelium
  • Genetic
  • Insulin signalling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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