title: Xanthine oxidase inhibition with febuxostat attenuates systolic overload-induced left ventricular hypertrophy and dysfunction in mice.
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-Akt(Ser473)), p42/44 extracellular signal-regulated kinase (p-Erk(Thr202/Tyr204)), and mammalian target of rapamycin (mTOR) (p-mTOR(Ser2488)). XO inhibition with febuxostat (5 mg/kg/d by gavage for 8 days) beginning approximately 60minutes after TAC attenuated the TAC-induced LV hypertrophy and dysfunction. Febuxostat blunted the TAC-induced increases in nitrotyrosine (indicating reduced myocardial oxidative stress), p-Erk(Thr202/Tyr204), and p-mTOR(Ser2488), with no effect on total Erk or total mTOR. Febuxostat had no effect on myocardial p-Akt(Ser473) 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.
authors.affiliation: Cardiovascular Division and Center of Vascular Biology, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.forename: Zhongbing
authors.initials: Z
authors.lastname: Lu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Wessale
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000069465:Febuxostat; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013599:Systole / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology
chemical_list: D013844:Thiazoles; D000069465:Febuxostat