Abstract 16552: hHO-1 Overexpression is Cardioprotective After Acute Myocardial Infarction - Differences Between Pigs and Mice
Heme oxygenase-1 (HO-1) responds to stress by increased production of bilirubin, carbon monoxide and free iron. These reaction products attenuate oxidative stress, inflammation and apoptosis, all of which play a role in ischemia/reperfusion injury. Therefore, we investigated he cardioprotective potential of human HO-1 overexpression.
Methods: Transgenic pigs (TG) were produced via somatic cell nuclear transfer. Pigs (wt, hHO-TG ± ZNPP, wt + adeno-associated virus (rAAV)-hHO-1 underwent LAD occlusion (I, 60min) and reperfusion (R, 24h). Apoptosis, leukocyte influx, capillary density, infarct size and myocardial function were assessed. Mice (HO-1 -/-, HO-1 +/+ +/- rAAV injection) underwent 45 min I/ 24h R. Global myocardial function (via Millar pressure tip catheter), infarct size (via SPECT and TTC staining) and inflammation were analyzed.
Results: Infarct size in mice was not different between HO-1 -/- and HO-1 +/+ mice (28±3 and 28±2 % of left ventricle), whereas overexpression of HO-1 via AAV clearly reduced the infarct size (20±3 %).Quantification of CD45 + cells revealed no differences between all three groups (HO-1 -/- 20±1 HO-1 +/+ 23±1; HO-1 -/- rAAV 23±1 cells/hpf). Myocardial function was clearly dependent on HO-1 expression in the ischemic myocardium. hHO-1 overexpression significantly reduced inflammation (874±66 (TG); 888±72 (rAAV) vs. 1611±180 (wt) leukocytes/mg tissue) in the ischemic area. Infarct size (35%±4 (TG); 45±2 (rAAV) vs. 63%±4 (wt)) was reduced and improved global and regional myocardial function (LVEDP 9±0.3 (TG); 9±0.2 (rAAV) vs. 11.9±1 mmHg (wt)). Moreover, apoptosis rate was reduced and capillary density was enhanced in the ischemic tissue after HO-1 overexpression. These effects were sensitive to the specific HO1 inhibitor ZNPP. In vitro, the over expression of HO-1 in myocytes enhanced myocytes survival and reduced endothelial cell apoptosis.
HO-1 is cardioprotective after acute myocardial infarction. Even though HO-1 overexpression is protective in both models (mice and pigs), mechanisms are different, since inflammation, which plays a major role in ischemia reperfusion injury in humans, was significantly influenced in pigs, but not altered in mice.
- © 2013 by American Heart Association, Inc.