Abstract 2942: Chronic Chymase Inhibition Improves Cardiac Dysfunction Through the Suppression of Excessive Oxidative Stress in Heart Failure
Reactive oxygen species (ROS) causes subcellular abnormalities, leading to cardiomyopathic changes, depressed contractile function and heart failure (HF). Cardiac angiotensin (Ang)-II, which is generated via both angiotensin-converting enzyme (ACE) and chymase, has been reported to be one of the major sources of ROS in the failing heart. However, it is unknown whether the chymase inhibition may affect ROS production in the progression of HF. We evaluated the chronic effects of a specific chymase inhibitor (TEI, 100mg/kg/day; n = 6), on cardiac function and superoxide anion (O2-) production in tachycardia-induced HF dogs (270ppm, 3weeks). Cardiac function markedly deteriorated accompanied with the enhanced O2- production after the induction of severe HF. However, TEI significantly decreased the left ventricular diastolic pressure and the cardiac collagen deposition. The compound decreased the cardiac Ang II production by 33% compared with the vehicle (p < 0.05) and the inhibitor significantly decreased the O2- production (vehicle 92.5 vs. TEI 57.9 RLU/min/mg, p < 0.05) in the failing left ventricle assessed by lucigenin-enhanced chemiluminescence. Cardiac gene expressions of chymase and transforming growth factor beta, a proinflammatory cytokine, evaluated by the real-time PCR markedly upregulated in HF, however, TEI attenuated those gene expression in HF. In conclusion, cardiac chymase contributes to the increased oxidative stress in HF and the chronic inhibition of chymase will become one of the therapeutic targets in the treatment of HF.