Abstract 3673: A Novel Mechanism for Akt2 in Ischemic Myocardial Repair: Limiting Macrophage Density
Background: Restoring blood flow to previously ischemic regions initiates tissue repair, partly by accelerated inflammatory reactions. Akt protein kinase promotes cell survival and reduces infarct size, but whether Akt regulates inflammatory response in ischemic tissue repair is not clear. To elucidate the role of Akt in inflammatory response after ischemic injury, mice with Akt2 gene ablation (Akt2-KO) were used.
Results: We induced myocardial infarction in WT and Akt2-KO mice by temporary occluding the left anterior descending coronary artery for 30 minutes followed by reflow. Akt2-KO myocardium displayed higher apoptotic activity (Tunel Index: WT 0.07±0.01 vs. Akt2-KO 0.12±0.01, p<0.05) and exhibited larger infarct size (WT 15.5% LV vs. Akt2-KO 23.4% LV, p<0.05). One week after infarction, immunohistochemistry staining showed similar endothelial cell density but a dramatic increase in macrophage density within the infarcted area of Akt2-KO myocardium (WT 113.2±29.8 cells/um2, Akt2-KO 234.7±24.7 cells/um2, p<0.05). Compared to WT ischemic controls, expression of macrophage functional markers was much higher in Akt2-KO hearts (Galectin-3, 3.3 fold; monocyte chemotactic-protein-1, 3.11 fold; TGFβ, 3.0 fold, when compared to WT controls, P<0.05). Four weeks after infarction, Akt2-KO myocardium developed larger ventricular scar and myocyte hypertrophy. Cardiac function, as evaluated by echocardiogram, was significantly worse in post-ischemic Akt2-KO mice than WT mice (WT 25.0±0.9 vs. Akt2-KO 19.0±2.1 FS% P<0.05). Since larger infarct size may account for elevated macrophage density in Akt2-KO hearts, we produced equivalent myocardial damage by a metal probe cooled with liquid nitrogen. Despite cryo-infarcted myocardium area was similar between WT and Akt2-KO mice (WT 33% LV vs. Akt2-KO 36% LV at 7 days), macrophages density remained elevated in Akt2-KO myocardium (WT 132.3+/−33.0 cells/um2 vs. 308.6+/−34.9 cells/um2).
Conclusion: Our data indicate a novel mechanism for Akt2 in tissue repair by limiting macrophage migration to previously ischemic myocardium.
This research has received full or partial funding support from the American Heart Association, National Center.