Dysregulated Oxalate Metabolism in Macrophages in Atherosclerosis

In this study, using targeted metabolomics, we identified decreased ratios of glycine to its precursors or related metabolites, serine, threonine, and oxalate, in patients with coronary artery disease (CAD). As found in patients with CAD, the glycine/oxalate ratio was significantly decreased in atherosclerotic Apoe-/- mice that showed suppression of hepatic AGXT. Utilizing genetic and dietary approaches to manipulate oxalate in Apoe-/- mice combined with studies in isolated macrophages, we demonstrate that increased oxalate exposure drives accelerated atherosclerosis in relation with dysregulated redox homeostasis, an increased inflammatory response, and enhanced hypercholesterolemia. The therapeutic potential of targeting dysregulated oxalate metabolism in atherosclerosis was studied using adeno-associated virus (AAV)-mediated overexpression of AGXT in Apoe-/- mice that showed lower oxidative stress, inflammation, and atherosclerosis. Thus, by studying impaired glycine metabolism in patients and mice with atherosclerosis and using mouse models to manipulate oxalate, we identified dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs