Loss of the Coronary Artery Disease Risk Gene <i>Leiomodin1</i> in Vascular Smooth Muscle Cells Triggers Rapid Onset Coronary Atherosclerosis

<b>What is new?:</b> Vascular smooth muscle cell (VSMC) loss of <i>Leiomodin1</i> ( <i>Lmod1</i> ) causes diffuse and occlusive coronary atherosclerosis in mice, with little or no such disease in other vascular beds. A novel immunogold lineage tracing assay shows VSMC migration to the intima as early as six days following an atherogenic regimen, and quantitative studies demonstrate that 46% of coronary plaque cells are of SMC origin.The coronary phenotype appears to be independent of LMOD1's actin nucleation activity, but VSMC lipid uptake is thrombospondin-dependent.<b>What are the clinical implications?:</b> LMOD1 is an annotated smooth muscle cell-restricted risk allele for human coronary artery disease (CAD), offering new insight into the role of smooth muscle cells in atherogenesis. The rapidly manifesting CAD phenotype in <i>Lmod1</i> knockout mice enables expedited testing of novel therapeutics to mitigate disease progression. New insight into LMOD1 pathobiology will help inform further SNV interrogation of the <i>LMOD1</i> locus for CAD risk in patients.