Xanthine Oxidase Inhibition With Febuxostat Attenuates Systolic Overload-Induced Left Ventricular Hypertrophy and Dysfunction in Mice

Xin Xu, Xinli Hu, Zhongbing Lu, Ping Zhang, Lin Zhao, Jerry L. Wessale, Robert J. Bache, Yingjie Chen

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

The purine analog xanthine oxidase (XO) inhibitors (XOIs), allopurinol and oxypurinol, have been reported to protect against heart failure secondary to myocardial infarction or rapid ventricular pacing. Because these agents might influence other aspects of purine metabolism that could influence their effect, this study examined the effect of the non-purine XOI, febuxostat, on pressure overload-induced left ventricular (LV) hypertrophy and dysfunction. Transverse aortic constriction (TAC) in mice caused LV hypertrophy and dysfunction and increased myocardial nitrotyrosine at 8 days. TAC also caused increased phosphorylated Akt (p-AktSer473), p42/44 extracellular signal-regulated kinase (p-ErkThr202/Tyr204), and mammalian target of rapamycin (mTOR) (p-mTORSer2488). XO inhibition with febuxostat (5 mg/kg/d by gavage for 8 days) beginning approximately 60 minutes after TAC attenuated the TAC-induced LV hypertrophy and dysfunction. Febuxostat blunted the TAC-induced increases in nitrotyrosine (indicating reduced myocardial oxidative stress), p-ErkThr202/Tyr204, and p-mTORSer2488, with no effect on total Erk or total mTOR. Febuxostat had no effect on myocardial p-AktSer473 or total Akt. The results suggest that XO inhibition with febuxostat reduced oxidative stress in the pressure overloaded LV, thereby diminishing the activation of pathways that result in pathologic hypertrophy and contractile dysfunction.

Original languageEnglish (US)
Pages (from-to)746-753
Number of pages8
JournalJournal of cardiac failure
Volume14
Issue number9
DOIs
StatePublished - Nov 2008

Bibliographical note

Funding Information:
This study was supported by a research grant awarded by TAP Pharmaceutical Products Inc, and by National Institutes of Health grants HL71790 and HL21872. PZ received a Scientist Development Award from American Heart Association, National Center.

Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.

Keywords

  • Left ventricular dysfunction
  • myocardial hypertrophy
  • pressure overload
  • xanthine oxidase inhibition

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