Vascular dysfunction in type 2 diabetic TallyHo mice: Role for an increase in the contribution of PGH2/TxA2 receptor activation and cytochrome p450 products

Zhong Jian Cheng, Yan Fen Jiang, Hong Ding, David Severson, Chris R. Triggle

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

In this study, we tested the hypothesis that spontaneously diabetic TallyHo (TH) mice, a novel polygenic model for type 2 diabetes, will exhibit endothelial dysfunction associated with an increased contribution from endothelium-derived contractile factors (EDCF). The cellular mechanisms underlying the increased contribution of EDCF were explored in 16 and 30-week-old male TH and age-matched male C57BL/6J mice (n = 4-9). Blood glucose and serum lipid profiles were markedly increased in the TH mice. Superoxide generation, assessed with a lucigenin chemiluminescence assay, was markedly increased in the aortae of TH mice. Endothelium-dependent vascular relaxations and contractions to acetylcholine (ACh), but not endothelium-independent relaxations to sodium nitroprusside, were impaired and vascular contractions to phenylephrine were significantly enhanced in aortae from TH mice. Nω-nitro-L-arginine methyl ester markedly increased the ACh-induced contractions in TH mice, whereas SQ29548, a thromboxane receptor antagonist, and cytochrome P450 (CYP) inhibitors 17-octadecynoic acid and sulfaphenazole, the latter being specific for CYP2C6 and 2C9, decreased and (or) normalized the contractile response to ACh in TH mice. The present study indicates that enhanced contribution of prostaglandin H2/thromboxane A2 receptor and CYP, likely CYP2C6 and 2C9, play a critical role in the pathogenesis of increased EDCF in the aortae of type 2 diabetic TH mice.

Original languageEnglish
Pages (from-to)404-412
Number of pages9
JournalCanadian Journal of Physiology and Pharmacology
Volume85
Issue number3-4
DOIs
Publication statusPublished - 1 Mar 2007

    Fingerprint

Keywords

  • Cytochrome P450 enzymes
  • Endothelium-dependent contraction
  • Endothelium-derived contracting factor
  • Prostaglandin H/thromboxane A receptor
  • Type 2 diabetes

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

Cite this