Abstract 14947: Cardiac-specific Expression of iNOS using an AAV9 Vector in Combination with the Cardiac Troponin-T Promoter Inhibits LV Remodeling after Reperfused Myocardial Infarction
Objectives: Expression of inducible nitric oxide synthase (iNOS) is dramatically increased in the heart after myocardial infarction (MI). Previous reports on the role of iNOS in post-MI left ventricular (LV) remodeling have yielded conflicting results. We sought to determine the long-term effect of cardiomyocyte-specific overexpression of iNOS initiated prior to reperfused MI and LV remodeling.
Methods: AAV9 vectors expressing iNOS or eGFP from the cardiac troponin-T (cTnT) promoter (AcTnTiNOS; AcTnTeGFP) were injected into 5 wk-old C57BL/6 mice (n=7) via jugular vein (3×10e11 vp/mouse). iNOS expression was assessed by Western blot, immunostaining and plasma nitrite. Four weeks post vector injection, chronic MI was induced by 60 min coronary occlusion followed by reperfusion. Cardiac magnetic resonance imaging (MRI) was performed at baseline (4 wk post vector injection) and on days 1, 7 & 28 after MI to assess LV volumes and ejection fraction (EF).
Results were compared to untreated wild type (WT, n=12) and AcTnTeGFP treated (n=5) mice. Results: Systemic injection of AcTnTiNOS elevated cardiomyocyte iNOS expression uniformly throughout the heart (by immunostain) and increased total cardiac iNOS expression at baseline by 16-fold relative to untreated WT (by Western). On day 1 post-MI, infarct size by Gd-enhanced MRI was similar in iNOS, WT & eGFP groups. At baseline, day 1 & day 7 post-MI; LV volumes were not significantly different between WT, eGFP & iNOS groups (Panel A). However, at day 28 post-MI, the iNOS group had smaller LV volumes compared to the WT or eGFP groups (LVEDV: 50.1 ± 3.7 vs 85.0 ± 3.5 and 74.4 ± 4.4 μ l, p<0.001; LVESV: 29.5 ± 3.5 vs 61.2 ± 3.3 and 50.5 ± 4.1 μ l, p<0.001; Panel B). Day 28 EF was also significantly higher in iNOS mice compared to WT (41.7 ± 2.8 vs 29.2 ± 2.6, p<0.01, Panel B).
Conclusion: Pre-established cardiomyocyte-specific overexpression of iNOS has no effect on the initial size of MI, but significantly reduces post-MI LV remodeling in mice. .
- © 2012 by American Heart Association, Inc.