Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis

Dysregulated glycine metabolism is emerging as a common denominator in cardiometabolic diseases, but its contribution to atherosclerosis remains unclear. In this study, we demonstrate impaired glycine-oxalate metabolism through alanine-glyoxylate aminotransferase (AGXT) in atherosclerosis. As found in patients with atherosclerosis, the glycine/oxalate ratio is decreased in atherosclerotic mice concomitant with suppression of AGXT. Agxt deletion in apolipoprotein E-deficient (Apoe−/−) mice decreases the glycine/oxalate ratio and increases atherosclerosis with induction of hepatic pro-atherogenic pathways, predominantly cytokine/chemokine signaling and dysregulated redox homeostasis. Consistently, circulating and aortic C-C motif chemokine ligand 5 (CCL5) and superoxide in lesional macrophages are increased. Similar findings are observed following dietary oxalate overload in Apoe−/− mice. In macrophages, oxalate induces mitochondrial dysfunction and superoxide accumulation, leading to increased CCL5. Conversely, AGXT overexpression in Apoe−/− mice increases the glycine/oxalate ratio and decreases aortic superoxide, CCL5, and atherosclerosis. Our findings uncover dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis. [Display omitted] •The glycine/oxalate ratio is reduced in both patients and mice with atherosclerosis•Loss of AGXT and dietary oxalate overload increase atherosclerosis in Apoe−/− mice•In macrophages, oxalate induces mitochondrial dysfunction, enhancing CCL5 release•AAV-AGXT treatment to target dysregulated oxalate metabolism lowers atherosclerosis Liu et al. show dysregulated glycine-oxalate metabolism in patients and mice with atherosclerosis. Oxalate overload due to loss of alanine-glyoxylate aminotransferase (AGXT) or hydroxy-l-proline supplementation aggravates pro-oxidant/inflammatory responses, hypercholesterolemia, and atherosclerosis. In macrophages, oxalate induces mitochondrial dysfunction and superoxide accumulation, enhancing CCL5 release. AGXT overexpression lowers pro-oxidant/inflammatory responses, reducing atherosclerosis.