Abstract 1596: Chronic NADPH Oxidase Inhibition Improves Cardiac Dysfunction Through The Suppression Of Cardiac Oxidative Stress And The Renin-Angiotensin System In Heart Failure
Excessive production of reactive oxygen species (ROS) causes subcellular abnormalities, leading to cardiomyopathic changes, depressed contractile function and heart failure (HF). Although cardiac NADPH oxidase and angiotensin II have been reported to be the major sources of ROS in the failing heart, it is unknown whether the chronic inhibition of the NADPH oxidase activity may affect cardiac function and the renin-angiotensin (RA) system in the progression of HF. We evaluated the chronic effects of a NADPH oxidase inhibitor, apocynin (15mg/kg/day; n=6), on cardiac function and the renin-angiotensin system in tachycardia-induced HF dogs (240ppm, 4weeks). Cardiac contractile function markedly deteriorated and cardiac fibrosis increased accompanied with the enhanced superoxide anion (O2-) production after the induction of severe HF. However, apocynin significantly improved the ejection fraction (vehicle 19% vs. apocynin 28%, p<0.01) and the inhibitor significantly decreased the enhanced O2-production (vehicle 78 vs. apocynin 40 RLU/min/mg, p<0.05) and NADPH oxidase activity (vehicle 3300 vs. apocynin 1400 RLU/min/mg, p<0.05) in the failing left ventricle assessed by lucigenin-enhanced chemiluminescence compared with the vehicle. Moreover, chronic apocynin inhibition decreased plasma renin activity (vehicle 10.5 vs. apocynin 2.6 ng/mL/hr, p<0.01) and aldosterone levels (vehicle 398 vs. apocynin 54 pg/mL, p<0.01) in HF. Cardiac gene expressions of NADPH oxidase subunits, gp91phox and p47phox, and ACE evaluated by the real-time PCR markedly upregulated in HF, however, apocynin attenuated those gene expression in HF. In conclusion, cardiac NADPH oxidase may interact with the RA system and increase oxidative stress in HF and the chronic specific inhibition of NADPH oxidase will become one of the therapeutic strategies in HF.