Abstract 436: Loss Of Serine Hydroxymethyltransferase 2 In Macrophages Enhances Atherosclerosis While Reducing Macrophage Mitochondrial Respiration

Abstract

Despite significant advancements in therapeutics and intervention, cardiovascular diseases remain the leading cause of death worldwide. Atherosclerosis, the accumulation of lipid-laden plaques in large arteries, is the underlying cause of most cardiovascular diseases. While the role of lipids is well-established in atherosclerotic cardiovascular disease, the contribution of amino acids is becoming increasingly recognized. Indeed, lower circulating glycine is consistently reported in patients with cardiovascular diseases. The mitochondrial serine hydroxymethyltransferase (SHMT2) is responsible for the bulk of glycine biosynthesis in most cell types. SHMT2 catalyzes the formation of glycine from serine and drives one-carbon metabolism necessary for mitochondrial protein translation. SHMT2 is critical in development since global knockout mice are nonviable. Previous studies showed patients with significant coronary artery disease exhibit a reduced glycine:serine ratio compared with healthy individuals. We discovered LPS-treated macrophages similarly attenuated glycine:serine concomitant with reduced SHMT2 expression. Moreover, we found SHMT2 is highly expressed in plaque-associated macrophages in both human and mouse atherosclerotic plaques. We hypothesized that SHMT2 regulates macrophage inflammatory phenotype in atherosclerosis through alterations in mitochondrial function. Deletion of SHMT2 reduced mitochondrial respiration while enhancing glycolysis similar to LPS-treated macrophages. In addition, SHMT2 deletion augmented oxidized-LDL accumulation in macrophages. To determine whether macrophage-expressed SHMT2 contributes to atherosclerosis, we applied CRISPR/Cas9 and Cre-lox recombination system to generate myeloid-specific SHMT2 knockout ( Shmt2 MKO ) mice. We further crossed Shmt2 MKO mice with Apoe knockout ( Apoe -/- ) mice to study atherosclerosis following Western diet feeding. Compared to littermate controls ( Shmt2 fl / Apoe -/- ), Shmt2 MKO / Apoe -/- mice had significantly enhanced plaque area. Our findings, representing the first investigation of conditional SHMT2 knockout mice, suggest a novel immunometabolic role for SHMT2 in macrophages in atherosclerosis.