GLS2 links glutamine metabolism and atherosclerosis by remodelling artery walls (aorta).

Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common in atherosclerotic cardiovascular disease. Here, we reveal that modulation of glutaminolysis or glutamate availability in culture media is critical for smooth muscle cell line (MOVAS) phenotypic switching. Cells were treated for 24 hours with glutaminase inhibitors (50mM DON, Sigma-SML0601) in presence or absence of 2mM glutamate suplementation (Gibco-35050061). High-throughput transcriptional profiling revealed that modulation of glutamine and glutamate homeostasis impacted genes involved in protein and extracellular matrix organization, cell motility and microtubule. Thus, we uncovered a novel role for glutamine metabolism in the phenotypic switch in SMCs, a hallmark of vascular remodelling. Overall design: Atherosclerosis-prone Ldlr-/- and Apoe-/- mice were backrossed with or without Gls2-/- mice. Then, hyperlipidemia was induced in these mice by feeding them with an atherogenic diet (Western diet, TD88137, Ssniff) for 12 weeks. Livers were obtained from all four genotypes and aortas were collected from Western died-fed Ldlr-/- and Ldlr-/-Gls2-/- mice.