Metformin confers longitudinal cardiac protection by preserving mitochondrial homeostasis following myocardial ischemia/reperfusion injury

Abstract

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.

The combination of Tanshinone IIA and Astragaloside IV attenuates myocardial ischemia–reperfusion injury by inhibiting the STING pathway

“…During the process of reperfusion, the abrupt reintroduction of oxygen to the mitochondria generates ROS, which exacerbates mitochondrial damage and triggers an inflammatory response, ultimately resulting in cell death [4,41]. Mitochondrial dysfunction plays a crucial role in the development of MIRI [42]. Numerous cardioprotective measures focus on mitochondria to reduce oxidative stress, inflammatory responses, and alleviate apoptosis [43][44][45].…”

Translocator Protein 18 kDa Tracer 18F-FDPA PET/CTA Imaging for the Evaluation of Inflammation in Vulnerable Plaques

“…For dynamic PET scanning in group A at 12 w (n = 5), intravenous anesthesia (propofol injection, 1 mg/kg body weight) was administered immediately after injection. Then, CT plain scans were performed to locate the aortic lumen, and the PET scan was conducted for 4 min (2 min/bed) at 4, 8,12,16,20,24,28,32,36,40,44,48,52,56, and 60 min postinjection, followed by contrast-enhanced computed tomography (CE-CT) using a PET/CT system (Biograph mCT, Siemens Healthcare, Erlangen, Germany). For the rest of the rabbits, intravenous anesthesia (Propofol injection, 1 mg/kg body weight) was administered 40 min postinjection; then, CT plain scans, PET scan, and CE-CT scan were conducted as mentioned above.…”

Effects of Metformin on Ischemia/Reperfusion Injury: New Evidence and Mechanisms

“…Myocardial TSPO expression was measured serially in correlation with the degree of mitochondrial homeostasis and cardiac function in a rat model exposed to myocardial I/R injury, using positron emission tomography imaging. The expression of TSPO was correlated with inflammatory changes in the infarcted area, and was associated with an upregulation of p-AMPK/AMPK; however, these effects were reversed with the use of metformin [ 70 ].…”