ArticleEuropean heart journal2023
Smooth muscle α-actin missense variant promotes atherosclerosis through modulation of intracellular cholesterol in smooth muscle cells.
Article in European heart journal, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 37 citations in OpenAlex.
- Atherosclerotic Cell Fates: A Single-Cell View of ER Stress.Journal of cardiovascular development and disease · 2026Review
- TRIM65 accelerates VSMC-derived foam cell formation and arteriosclerosis progression by inhibiting mitophagy.Molecular and cellular biochemistry · 2026Article
- Re-Purposing Sapropterin (Kuvan) for ACTA2-Related Multisystemic Smooth Muscle Dysfunction Syndrome: A Translational Mechanistic and First-In-Human Therapeutic Report.Annals of clinical and translational neurology · 2026Article
- Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.Signal transduction and targeted therapy · 2026Review
- Article
- Endothelial-to-mesenchymal transition in atherosclerosis: mechanisms, therapeutic targets, and future perspectives.Frontiers in cell and developmental biology · 2026Review
- Immune checkpoint inhibitor-driven smooth muscle cell phenotypic modulation: a potential contributor to atherosclerotic risk associated with these therapies.Frontiers in cardiovascular medicine · 2026Article
- Lipid infiltration promotes trans-differentiation of vascular smooth muscle cells into macrophage-like cells in early lesions of human coronary atherosclerosis.Lipids in health and disease · 2025Article
- NEXN regulates vascular smooth muscle cell phenotypic switching and neointimal hyperplasia.JCI insight · 2025Article
- Zebrafish navigating the metabolic maze: insights into human disease - assets, challenges and future implications.Journal of diabetes and metabolic disorders · 2025Review
- Mutational landscape of atherosclerotic plaques reveals large clonal cell populations.JCI insight · 2025Article
- Chronic inflammation and vascular cell plasticity in atherosclerosis.Nature cardiovascular research · 2024Review
- Use of iPSC-Derived Smooth Muscle Cells to Model Physiology and Pathology.Arteriosclerosis, thrombosis, and vascular biology · 2024Review
- The relationship between early-onset coronary artery disease and familial hypercholesterolemia: a cohort study based on the Hakka population in Meizhou, China.American journal of translational research · 2024Article
- Bioinformatics analysis of immune cell infiltration patterns and potential diagnostic markers in atherosclerosis.Scientific reports · 2023Article
- Pericentrin deficiency in smooth muscle cells augments atherosclerosis through HSF1-driven cholesterol biosynthesis and PERK activation.JCI insight · 2023Article
- Statins for ACTA2 mutation-driven atherosclerosis?European heart journal · 2023Article
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
aimsThe variant p.Arg149Cys in ACTA2, which encodes smooth muscle cell (SMC)-specific α-actin, predisposes to thoracic aortic disease and early onset coronary artery disease in individuals without cardiovascular risk factors. This study investigated how this variant drives increased atherosclerosis. METHODS AND
resultsApoe-/- mice with and without the variant were fed a high-fat diet for 12 weeks, followed by evaluation of atherosclerotic plaque formation and single-cell transcriptomics analysis. SMCs explanted from Acta2R149C/+ and wildtype (WT) ascending aortas were used to investigate atherosclerosis-associated SMC phenotypic modulation. Hyperlipidemic Acta2R149C/+Apoe-/- mice have a 2.5-fold increase in atherosclerotic plaque burden compared to Apoe-/- mice with no differences in serum lipid levels. At the cellular level, misfolding of the R149C α-actin activates heat shock factor 1, which increases endogenous cholesterol biosynthesis and intracellular cholesterol levels through increased HMG-CoA reductase (HMG-CoAR) expression and activity. The increased cellular cholesterol in Acta2R149C/+ SMCs induces endoplasmic reticulum stress and activates PERK-ATF4-KLF4 signaling to drive atherosclerosis-associated phenotypic modulation in the absence of exogenous cholesterol, while WT cells require higher levels of exogenous cholesterol to drive phenotypic modulation. Treatment with the HMG-CoAR inhibitor pravastatin successfully reverses the increased atherosclerotic plaque burden in Acta2R149C/+Apoe-/- mice.
conclusionThese data establish a novel mechanism by which a pathogenic missense variant in a smooth muscle-specific contractile protein predisposes to atherosclerosis in individuals without hypercholesterolemia or other risk factors. The results emphasize the role of increased intracellular cholesterol levels in driving SMC phenotypic modulation and atherosclerotic plaque burden.
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