Metformin Reduces Vascular Inflammation as Assessed by PET in a Mouse Model of Early Atherosclerosis

Abstract

Background: Atherosclerosis is the principal pathological substrate of cardiovascular events. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can assess inflammatory activity within plaques. It is unclear whether metformin acts mainly on early atherosclerotic plaque development or on existing lesion burden to stabilize vulnerable plaques. Moreover, longitudinal imaging to evaluate the stage-dependent antiatherosclerotic effects of metformin warrants further study. Methods: ApoE–/– mice were fed a Western diet for 20 weeks to induce atherosclerosis. In vivo and ex vivo 18F-FDG PET/CT imaging were used to longitudinally quantify 18F-FDG uptake in various aortic segments at 8, 12, and 20 weeks. Additionally, the study evaluated the effects of metformin at two dose levels (low: 250 mg/kg/d; high: 500 mg/kg/d) on plaque burden and inflammatory uptake at early and advanced atherosclerotic stages. Results: Aortic 18F-FDG uptake measured by PET/CT was associated with plaque burden and selected vulnerability-related pathological features. 18F-FDG uptake, quantified as both the average standardized uptake value (SUVmean) and the maximum standardized uptake value (SUVmax), was significantly positively correlated with plaque areas in the abdominal and thoracic aorta. Higher 18F-FDG uptake in the aortic arch was associated with greater plaque burden, more severe luminal stenosis, and increased macrophage-associated MMP13 and SSTR2 staining in aortic root sections. During early atherogenesis, metformin reduced vascular 18F-FDG uptake and plaque area, decreased necrotic core and fibrotic areas within plaques, and lowered serum total cholesterol and triglyceride levels. These changes were accompanied by increased aortic AMPKα phosphorylation. In aged ApoE–/– mice with advanced atherosclerosis, low-dose metformin reduced abdominal aortic SUVmean without significant changes in SUVmax or the mean target-to-background ratio (TBRmean). Neither dose significantly reduced 18F-FDG uptake in the thoracic aorta, ascending aorta, or aortic arch. Conclusions: Our findings support the potential value of 18F-FDG PET/CT for noninvasive assessment of disease activity and monitoring of treatment response in murine atherosclerosis. Metformin attenuated vascular inflammation and plaque formation during early atherogenesis, and these changes were associated with increased aortic AMPKα phosphorylation. In the advanced-stage model, treatment-associated reductions in vascular 18F-FDG uptake were not consistently detected. These findings suggest that the vascular effects of metformin may vary with disease stage.