Abstract 16376: Recruitment of Angiopoietin-i and Wnt10 Signaling by Activation of Ho-1 Restores Cardiac Function and Improves Angiogenesis in Infarcted Myocardium
Rationale: Post-ischemic cardiomyopathy and progressive decline in cardiac function has been partly ascribed to chronic inflammation and lack of significant response in angiogenesis and blood flow. Increased Heme oxygenase-1 (HO-1) gene expression plays an important role in the restoration of vascular function, decrease in endothelial cell death and sloughing. Previous studies have shown mice deficient in HO-1 expressed severe cardiac dysfunction and abnormal ventricular remodeling.
Objective: The aim of this study was to investigate whether HO-1 induction can reduce post ischemic cardiac remodeling by recruitment of angiogenesis molecules to the infarcted myocardium, thereby improving cardiac function by an increase in capillary formation in the ischemic site.
Methods: Post ischemic heart failure was induced by LAD ligation. C57Bl6 mice were divided into 4 groups: sham, myocardial infarction (MI), MI treated with the HO-1 inducer cobalt protoporphyrin (CoPP) with and without the HO-1 inhibitor, stannous mesoporphyrin (SnMP). Myocardial echocardiography was performed to assess the blood volume, velocity, LVend-diastolic and ejection fraction.
Results: HO-1 overexpression led to a significant increase in CD31+, EGF, Angiopoietin-1 and adiponectin levels (p<0.02 vs. MI) in plasma. Cardiac histological examination revealed a significant decrease in cardiac fibrosis and apoptosis and an increase in myocardial angiogenesis and capillary density (p<0.05 vs. MI). Echocardiography showed that left ventricle dilatation, measured as end diastolic area (EDA), was significantly reduced in CoPP treated groups compared to MI groups (EDA: MI: 0.216 ±0.02 cm; MI+CoPP: 0.172±0.03 cm; (-13%) p<0.01). Western blot analysis of cardiac tissues showed increased expression of the angiogenic markers Angiopoietin-1, VEGF and FGF along with a significant increase in WNT10b and SHH protein levels in CoPP treated mice compared to MI groups (p<0.02). These beneficial effects were reversed by SnMP.
Conclusion: Recruitment of Angiopoietin-I and WNT10 signaling by activation of HO-1 improves cardiac function and remodeling via induction of neovascularization, suppression of tissue inflammation and reduction in post ischemic infarct size.
- © 2012 by American Heart Association, Inc.