Abstract 4376: ACE and Chymase Inhibition Prevents the Cardiac Fibrosis Interacting with Cardiac Endothelin System in Heart Failure
Both the cardiac renin-angiotensin and endothelin (ET) systems are the strong stimulator of fibrosis in heart failure (HF) and integrally involved in the cardiac remodeling process. Angiotensin (Ang)-II is generated by not only ACE but also chymase in the heart. We have already revealed Ang-II not only through ACE but also via chymase pathway stimulates ET generation in the failing cardiac tissue. However, whether suppression of Ang-II generation using both ACE and chymase inhibitors modifies the cardiac collagen architecture in HF, affecting the ET system, has not yet been elucidated. We evaluated the long-term concomitant effects of an ACE inhibitor (ACEI) with a chymase inhibitor (ChyI) on cardiac structural changes, and several failing heart related genes comparing to a monotherapy of an ACEI alone in dogs with tachycardia induced HF. Some of our results are shown in the Table⇓. Not only ACE, chymase and preproET-1 mRNA, but also chymase-positive mast cells density evaluated by chymotrypsin staining increased in the failing heart. There was a significant positive correlation between the number of chymase-degranulated cells and the level of cardiac preproET-1 mRNA in the progression of HF. The concomitant inhibition more significantly decreased collagen accumulation and improved diastolic dysfunction compared to ACE inhibition alone accompanied with decrease in cardiac preproET-1 mRNA expression. In conclusion, concomitant blockade of Ang-II generation through not only ACE but also chymase pathway may prevent cardiac fibrosis and improve diastolic function, in part, via suppression of the ET system.