Role of Xanthine Oxidase in Hypertensive Heart Failure in Dahl Salt-sensitive Rats

Aims: Xanthine oxidase (XO) is one of the sources of superoxide production in cardiac myocytes. However, pathophysiological role of XO in hypertensive heart failure has not been clear. Thus, the present study examined impact of high salt intake and XO inhibition on cardiac hypertrophy and fibrosis in hypertensive Dahl salt-sensitive (Dahl-S) rats. Metods: 8-week old, male Dahl-S rats were fed a normal salt diet or a high salt diet for 8 weeks. A part of rats fed the HS diet were treated simultaneously with a XO inhibitor, febuxostat. Results: HS intake increased blood pressure and heart weight, and Fx diminished them. HS intake caused cardiomyocyte hypertrophy and interstitial fibrosis in left ventricle (LV), and FX ameliorated them. HS increased XO activity 4.7 fold and NADPH oxidase activity 1.5 fold, and Fx suppressed XO activity completely and NADPH oxidase activity by 80%. HS increased protein expression of XO, p47phox, angiotensin-converting enzyme, angiotensin II type 1 receptor, transforming growth factor-β1 and activation of extracellular signal-regulated kinase in LV, and Fx reduced them except XO. Conclusion: HS intake induces hypertension, LV hypertrophy and fibrosis with activation of XO, NADPH oxidase and renin-angiotensin (RA) system in Dahl-S rats. Fx inhibits not only XO but also NADPH oxidase and RA system, suggesting that XO inhibition may be an effective therapy for hypertensive heart failure.