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 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-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.