| Abstrakt: |
Introduction:Myocardial Infarction (MI) results in increased mitochondrial reactive oxygen species (mito-ROS), leading to endothelial dysfunction and maladaptive remodeling of left ventricle (LV). As Mitochondria plays a major role in fatty acid oxidation (FAO)-mediated nucleotide synthesis and proliferation in endothelial cells (EC), we wanted to examine whether EC-specific subcellular modulation of mito-ROS improves post-MI cardiac function by inducing coronary angiogenesis. To that end, we generated a binary conditional transgenic mouse model that overexpresses EC-specific mito-antioxidant MnSOD (MnSOD-OE), reducing mito-ROS.Hypothesis:We hypothesize that a decrease in endothelial mito-ROS improves post-MI cardiac function by increasing FAO-induced nucleotide synthesis resulting in coronary angiogenesis.Methods:Age (12 weeks)- and sex-matched MnSOD-OE mice underwent left anterior coronary artery ligation (n=8/group): The control group received 2mg/mL Tetracycline (Tet) in drinking water, whereas the experimental group (MnSOD-OE) received no Tet. LV ejection fraction (EF) and fractional shortening (FS) were assessed by echocardiography 28 days after surgery. The infarction area, angiogenesis and EC proliferation were examined by immunofluorescence and histology of ischemic LV. Mouse heart EC (MHEC) were isolated and cultured with (Control group) or without (MnSOD-OE group) Tet (2?g/mL). Assays for FAO, aspartate level, and activation of Akt were performed.Results:The EF and FS increased by 16?7.87% and 21.73?10.31%, respectively, in MnSOD-OE group (p<0.01). The infarction area was decreased by 40.82?22.44% in MnSOD-OE group (p<0.05). Ischemic myocardium in MnSOD-OE had higher capillary (4.13?4.10-fold, p<0.05) and arteriole (5.48?3.51-fold, p<0.001) density. PCNA assay showed increased EC proliferation in MnSOD-OE group (by 1.46?0.80fold, p<0.01) compared to the Control. FAO, aspartate levels, and activation of Akt were also increased by 65.78?24.30%, 46.24?19.46%, and 80.46?3.95% (p<0.05), respectively, in MnSOD-OE group.Conclusions:We conclude that decrease in EC mito-ROS increases FAO, and this metabolic shift induces coronary angiogenesis, which improves post-MI cardiac function. |
