Abstract 4835: Angiotensin-Converting-Enzyme 2 (rhACE2) Potently Attenuates the Negative Hemodynamic Effects of Angiotensin II (ATII) and Improves Post-Myocardial Infarction (MI) Remodeling
ATII is a potent vasoconstrictor involved in the pathophysiology of several diseases. Antagonizing the Renin-Angiotensin-Aldosterone-System (RAAS) is one of the key principles in the treatment of heart failure. ACE2, a recently discovered homologue of the Angiotensin-Converting-Enzyme (ACE), catalyzes the cleavage of ATII to Angiotensin (1–7) as well as other reactions. rhACE2 has proven to be therapeutic in a model of the Adult Respiratory Distress Syndrome (ARDS). This study has been planned to study the in-vivo hemodynamic effects of rhACE2 as well as its effects on post-MI remodeling. rhACE2 was produced in a mammalian expression system. Pressure-volume catheter measurements were carried out in male C57/Bl6N mice. Post-MI remodeling was studied by echocardiography in female C57/Bl6N mice after LAD-ligation. Bolus infusion of 2mg/kg rhACE2 (n=7) lead to a significant reduction of arterial elastance by 13.2±1.1% (p<0.01) paralleled by a modest drop in maximal systolic blood pressure from 93.4±4.2mmHg to 86.3±5.1mmHg (p<0.01). Stroke volume and cardiac output showed a strong trend (p=0.06 and 0.08 respectively) to increase after rhACE2-treatment. Following ACE2 (n=5) or vehicle infusion (n=8) ATII was infused at constant infusion rates from 0.2μg/kg/min to 40μg/kg/min. ACE2 pretreatment shifted the EC50 for the ATII induced increase in systolic blood pressure by almost one order of magnitude from 1.11μg/kg/min (CI 0.42 to 2.9) to 10.9μg/kg/min (CI 7.2 to 16.7) (p=0.014). Similarly the EC50 values for the ATII mediated decrease in ejection fraction and preload adjusted maximal power as well as the increase of end systolic volume were significantly shifted to higher ATII doses. To study post-MI remodeling mice were treated twice daily with intraperitoneal injections of 1mg/kg rhACE2. Echocardiography was performed 2 weeks following LAD. Mice treated with rhACE2 (n=15) showed a significantly improved fractional shortening (14.3±1.6%) compared to vehicle treated mice (10.3±1.1%, n=12, p=0.049). These data show that rhACE2 is highly potent in reducing the negative effects of ATII in vivo which might translate in improved post-MI remodeling. rhACE2 could become an alternative treatment option for several diseases related to an activated RAAS.