Upregulation of cardiac interstitial chymase after canine myocardial ischemia and reperfusion

Abstract

The serine protease chymase is stored in mast cell secretory granules and is released upon mast cell activation into the cardiac interstitium where it activates matrix metalloproteinases, causes cardiomyocyte apoptosis, and generates angiotensin (Ang) II. Miyazaki et. al. (Life Sci. 71:437, 2002) reported beneficial effects on cardiac function and survival of chymase inhibition during the acute phase of myocardial infarction in hamsters. Here we determined if mast cell‐chymase is released into the cardiac interstitium after acute myocardial ischemia (MI) and reperfusion in dogs. To measure in vivo left ventricle (LV) interstitial fluid (ISF) chymase activity, we combined cardiac microdialysis with direct ISF infusion of the chymase‐specific substrate [Pro11, DAla12]Ang I after MI. The ISF chymase activity in the ischemic region was 3.5‐fold (n=6, p<0.001) increased after 60 min MI followed 100 min reperfusion and it was significantly suppressed by TEI‐F00806 (100 mg/kg/BID, pretreated 5 days), a novel, orally active and specific chymase inhibitor (CI). Importantly, there was also 5‐fold (n=6, p<0.001) increased ISF chymase activity in the non‐ischemic region after reperfusion and this increase was completely blocked by CI treatment. The current investigation indicates that LV ISF chymase in vivo can be regulated by factors that affect mast cell activation, in particular, MI and reperfusion. These findings demonstrated for the first time that cardiac interstitial chymase participates directly in the pathophysiologic state after acute MI in dog. Supported by TEIJIN Pharma Limited and SCCOR in Cardiac Dysfunction P50HL077100 (LJD).