Aspirin resistance with genetic dyslipidemia: Contribution of vascular thromboxane generation

Jefferson C. Frisbee, Adam G. Goodwill, Phoebe A. Stapleton, Stephanie J. Frisbee, Alexandre C. D'Audiffret

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

One clinical intervention against the negative outcomes associated with atherothrombotic vascular disease (AVD) is low-dose, chronic aspirin therapy. However, epidemiological studies suggest that recurrence of adverse vascular events with aspirin therapy is growing and associated with therapy duration. The contributors to this outcome are unclear and include poor patient compliance and aspirin-resistant platelet thromboxane A2 (TxA2) production. Based on previous results in hypercholesterolemic mice, we hypothesized that elevated aspirin-insensitive arachidonic acid (AA)-induced TxA2 production by the vascular endothelium contributes to aspirin resistance in AVD independent of platelet behavior. AA-induced dilation was blunted in aortic rings and in arterioles from apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) gene deletion mice (vs. C57/Bl6/J), partially due to elevated TxA2 production. Acute inhibition of cyclooxygenases or TxA2 synthase attenuated the increased TxA 2 production in ApoE and LDLR and improved AA-induced dilation, responses that were mirrored by chronic treatment with low-dose aspirin of 16 wk duration. However, this effect was not temporally stable, and, with longer-duration therapy, the beneficial impact of aspirin on outcomes diminished. A similar, though less robust, pattern to the impact of chronic aspirin therapy on vascular outcomes was identified with chronic antioxidant treatment (TEMPOL). These results suggest that in dyslipidemic mice, the beneficial impact of chronic aspirin therapy on improving vascular outcomes decay with time and that a contributing element to subsequent negative vascular events may be the development of aspirin-resistant TxA2 production by the vasculature itself.

Original languageEnglish (US)
Pages (from-to)331-341
Number of pages11
JournalPhysiological genomics
Volume42
Issue number3
DOIs
StatePublished - Aug 1 2010

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Genetics

Keywords

  • Arachidonic acid metabolism
  • Atherothrombotic vascular disease
  • Peripheral vascular disease
  • Regulation of vascular tone

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