Abstract 8978: NADPH Oxidase Inhibition Improves Cardiac Dysfunction Through Cardiac Mast Cell Stabilization and Suppression of the Renin-Angiotensin System
Reactive oxygen species (ROS) participate in the pathogenesis of cardiac inflammation and the activation of the renin-angiotensin (RA) system in the progression of heart failure (HF). NADPH oxidase is one of the major sources of the ROS production. Mast cells migrated into the failing heart mainly recruited by the locally produced chemokine, stem cell factor, and are involved in the inflammatory process since they generate various substances such as not only chymase which is an ACE independent angiotensin-II formation enzyme but also tumor necrotic factor (TNF)-alpha and transforming growth factor (TGF)-beta in HF. However, It has not been well documented whether NADPH oxidase inhibition affects cardiac inflammatory changes via mast cells and the RA system in HF. Thus, we evaluated the long-term effects of a specific NADPH oxidase inhibitor; apocynin (15mg/kg/day; n=6) on changes in cardiac function and the expression of several inflammatory related genes in dogs with tachycardia induced HF. Cardiac contractile function markedly deteriorated and left ventricular (LV) end-diastolic pressure (EDP) was increased after the induction of HF. However, apocynin significantly improved the ejection fraction and decreased the elevated LVEDP. The inhibitor significantly decreased the enhanced superoxide production (vehicle 78 vs. apocynin 40RLU/min/mg, p<0.05) and NADPH oxidase activity (vehicle 3300 vs. apocynin 1400RLU/min/mg, p<0.05) in the LV assessed by lucigenin-enhanced chemiluminescence compared with the vehicle. Cardiac ACE and NADPH oxidase subunits, gp91phox and p47phox, gene expressions significantly upregurated in HF, however, apocynine attenuated those gene activation. Moreover, apocynine decreased the number of the infiltrated mast cells and suppressed the mRNA of stem cell factor, chymase, TGF-beta, TNF-alpha in the failing heart. In conclusion, specific NADPH oxidase inhibition may become an important strategy in the treatment of cardiac dysfunction via mast cell stabilization and the suppression of RA system.
- © 2011 by American Heart Association, Inc.