Abstract 1706: The Shift in Arginine Utilization from iNOS to Arginase is Critical in Limiting Infarct Expansion after Reperfused Myocardial Infarction
Introduction: Arginine metabolism is tightly regulated during scar formation, with NO production by iNOS during the acute phase and ornithine production by arginase during the repair phase. LV remodeling post-MI is nearly absent in iNOS-/- mice, but the mechanism has yet to be defined. We hypothesized that arginase activity would be enhanced in iNOS-/- mice post-MI, which could hasten tissue repair thus preserving LV structure and function.
Methods: 38 C57Bl/6 (B6) and 38 congenic iNOS-/- mice were used. MI was induced by a reperfused 1hr LAD occlusion. LV end-systolic volume (LVESV), ejection fraction (EF) and wall thickness were assessed by MRI. Myocardial nitrate/nitrite (NOx) levels and arginase activity were measured in normals and at Day 1, 3, 5, 7, 14, 21 & 28 post-MI.
Results: By Day 28 post-MI; LVESV in B6 mice increased to 56±19μl, EF declined to 32±10% and scar tissue subtended 32±4% of the LV circumference. By Day 28 in iNOS-/- mice with similar infarct size, LVESV increased to only 35±9, EF declined to only 41±9 and scar tissue subtended only 11±2% of the LV (all p<0.05 vs B6 at Day 28). In B6 mice, levels of myocardial NOx peaked at Day 1 (p<0.05 vs bsl) and declined sharply by Day 3 post-MI. In contrast, the peak of NOx in iNOS-/- mice was delayed by 2 days and was significantly blunted (p<0.05 vs B6 peak). Myocardial arginase activity in B6 mice peaked at nearly 200x baseline on Day 5 post-MI. In iNOS-/- mice, myocardial arginase attained a similar peak on Day 3, a full 2 days earlier than in B6 mice.
Conclusion: Deletion of iNOS blunts the peak of NOx production and hastens the activation of arginase, consistent with early tissue repair and preservation of LV structure and function in iNOS-/- mice.