Loss of the Coronary Artery Disease Risk Gene <i>LMOD1</i> in Vascular Smooth Muscle Cells Triggers Rapid-Onset Coronary Atherosclerosis.
basic_science · Level V
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- Record sourced from PubMed, PMID 42549503.
- Also identified by DOI 10.1161/CIRCULATIONAHA.126.080105.
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Abstract
Atherosclerosis is the primary underlying cause of coronary artery disease. <i>LMOD1</i> is a coronary artery disease risk gene whose role in coronary artery pathophysiology is unknown. Whole-body loss of <i>Lmod1</i> causes a lethal neonatal visceral myopathy in mice, necessitating unique approaches for the study of vascular smooth muscle cell (VSMC) phenotypes. Control mice (<i>Lmod1<sup>WT</sup></i> carrying a Cre recombinase allele) and VSMC-restricted <i>Lmod1</i> knockout mice (<i>Lmod1<sup>SMKO</sup></i>) were subjected to various atherogenic regimens. Atherosclerosis and LMOD1 (leiomodin 1) expression in mouse and human coronary arteries were assessed by histopathology and confocal immunofluorescence microscopy. Coronary arteries from <i>Lmod1</i><sup><i>WT</i></sup> and <i>Lmod1</i><sup><i>SMKO</i></sup> mice were analyzed with assorted stains and antibodies, immunogold lineage tracing, and spatial metabolomics. Aortic smooth muscle cells from <i>Lmod1<sup>WT</sup></i> and <i>Lmod1</i><sup><i>SMKO</i></sup> mice were subjected to lipid loading with or without lentivirus carrying wild-type or actin nucleation-deficient <i>Lmod1</i> (<i>Lmod1<sup>ND</sup></i>. Mice harboring an intronic deletion of <i>Lmod1</i> or <i>Lmod1</i><sup><i>ND</i></sup> were engineered using clustered regularly interspaced short palindromic repeats. A lethal neonatal visceral myopathy occurred in <i>Lmod1</i><sup><i>SMKO</i></sup> mice using <i>Myh11-CreER</i><sup><i>T2</i></sup>, prohibiting further investigation. In contrast, <i>Lmod1</i><sup><i>SMKO</i></sup> mice generated with <i>Itga8-CreER</i><sup><i>T2</i></sup> survived and were therefore used in all subsequent studies. Under atherogenic conditions, <i>Lmod1</i><sup><i>SMKO</i></sup> mice displayed little vascular disease in several organs but developed diffuse, occlusive coronary atherosclerosis with fibrous caps. No such disease was observed in <i>Lmod1</i><sup><i>WT</i></sup> mice. Time-course studies documented lipid insudation and VSMC migration into the intima of coronary arteries of <i>Lmod1</i><sup><i>SMKO</i></sup> mice as early as 8 days after the regimen. Immunogold lineage tracing revealed that 46% of coronary plaque cells were of VSMC origin. Spatial metabolomics uncovered multiple lipid species within coronary atheromata of <i>Lmod1</i><sup><i>SMKO</i></sup> mice. In vitro studies demonstrated elevated lipid accumulation in <i>Lmod1</i><sup><i>SMKO</i></sup> VSMCs, which was rescued by viral-mediated <i>Lmod1</i><sup><i>WT</i></sup> or <i>Lmod1</i><sup><i>ND</i></sup> expression. An intronic deletion of <i>Lmod1</i>, comprising a conserved orthologous sequence where the single nucleotide variant associated with coronary artery disease exists, showed attenuated LMOD1 expression. Heterozygous <i>Lmod1</i><sup><i>SMKO</i></sup> mice, with a comparable reduction in LMOD1, displayed no coronary artery disease. Similarly, VSMC-restricted expression of <i>Lmod1</i><sup><i>ND</i></sup> resulted in negligible coronary atherosclerosis. Under atherogenic conditions, <i>Lmod1</i><sup><i>SMKO</i></sup> mice present with rapid-onset coronary atherosclerosis. LMOD1 safeguards coronary homeostasis, apparently in an actin nucleation-independent manner.