Myocardial ischemia-reperfusion (I/R) injury is associated with systemic oxidative stress, cardiac mitochondrial homeostasis, and cardiomyocyte apoptosis. Metformin was recognized to attenuate cardiomyocyte apoptosis. However, the longitudinal effects and pathomechanism of metformin on the regulation of myocardial mitohormesis following I/R treatment remain unclear. The aim of this study was to investigate the longitudinal effects and mechanism of metformin in regulating cardiac mitochondrial homeostasis by serial imaging with the 18-kDa translocator protein (TSPO)-targeted positron emission tomography (PET) tracer 18 F-FDPA.
MethodsMyocardial I/R injury was established in Sprague-Dawley rats, which were treated with or without metformin (150 mg/kg per day). Serial gated 18 F-FDG and 18 F-FDPA PET imaging were performed at 1, 4, and 8 weeks after surgery, followed by analysis of ventricular remodelling and cardiac mitochondrial homeostasis. After PET imaging, the activity of antioxidant enzymes, immunostaining, and western blot analysis were performed to analyse the spatio-temporal effects and pathomechanism of metformin for cardiac protection after myocardial I/R injury.
ResultsOxidative stress and apoptosis increased one week after myocardial I/R injury (before signi cant progression of ventricular remodelling). TSPO co-localized with in ammatory CD68 + macrophages in the infarct area, and upregulation of AMPK-p/AMPK and down-regulation of Bcl-2/Bax were observed. However, these effects were reversed with metformin treatment. Eight weeks after myocardial I/R injury (representing the advanced stage of heart failure), 18 F-FDPA uptake activity in myocardial cells in the distal non-infarct area increased without CD68 + expression, whereas the activity decreased with metformin treatment.
ConclusionTaken together, these results show that prolonged metformin treatment has pleiotropic protective effects against myocardial I/R injury associated with a regional and temporal dynamic balance between mitochondrial homeostasis and cardiac outcome, which were assessed by TSPO-targeted imaging during cardiac remodelling.
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