Abstract 14474: Chymase Inhibition Reduces Myocardial Infarction and Matrix Metalloproteinase-9 Activation Following Acute Ischemia/Reperfusion
Introduction: Chymase, an enzyme in the renin-angiotensin system (RAS) that generates angiotensin II, is involved in the activation of matrix metalloproteinase-9 (MMP-9) and myocardial remodeling. We investigated the effect of chymase inhibition on myocardial protection, the RAS pathway and MMP-9 activation in the setting of acute myocardial ischemia/reperfusion (AMI-R).
Methods: Fourteen Yucatan pigs underwent 60 min of mid-left anterior descending coronary artery occlusion followed by 120 min of reperfusion and received intravenously either vehicle (V, n = 7) or chymase inhibitor (CM-I, n = 7) as a bolus 50 min into ischemia followed by a continuous infusion during reperfusion. Monastryl blue/triphenyl tetrazolium chloride staining was used to identified the area-at-risk (AAR) and infarction. Western blotting, ELISA and TUNEL staining were performed. Myocardial chymase activity was measured in vitro using a specific synthetic substrate.
Results: Infarct size expressed as a % of AAR was significantly lower in CM-I than V (V:41±5, CM-I: 24±5, p < 0.01), whereas the size of the AAR was similar between groups (V: 36±3, CM-I: 37±2, p = 0.77). No significant difference was observed in LV function between V and CM-I. Myocardial levels of Chymase (p = 0.01), cleaved MMP-9 (p < 0.0001), cleaved/pro MMP-9 (p = 0.02), phospho/total Akt (p < 0.01), phospho-Bad (p = 0.03), total Bad (p = 0.04), phospho-Erk (p = 0.01), phospho-GSK3beta (p < 0.01), total GSK3beta (p = 0.04) in the AAR were significantly lower in CM-I than V, whereas phospho-eNOS (p < 0.01) and total eNOS (p = 0.03) were significantly higher in CM-I than V. Serum Troponin T at the end of reperfusion was significantly lower in CM-I than V (p = 0.03). TUNEL-positive cell count in the AAR was 4.3-fold higher in V versus CM-I (V: 63±20, CM-I: 14±5, p = 0.05). Chymase activity in both AAR (p = 0.01) and non-ischemic area (p = 0.02) was significantly lower in CM-I than V.
Conclusions: This study demonstrates that chymase inhibition plays an important role in myocardial protection during AMI-R and reduces myocardial MMP-9 activity. This suggests that chymase inhibition may not only provide improved myocardial protection but may also modify LV remodeling induced by AMI-R.
- © 2010 by American Heart Association, Inc.