ArticleArteriosclerosis, thrombosis, and vascular biology2020
Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
49 citing papers in PubMed, 2 syntheses or guidelines pooled it, 70 citations in OpenAlex.
- Macrophage-associated kinase signaling in atherosclerosis - a systematic review.Cell communication and signaling : CCS · 2026Pooled it
- Coronary Artery Calcification Under Statin Therapy and Its Effect on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.Frontiers in cardiovascular medicine · 2020Pooled it
- Vascular calcification: pathogenic mechanisms, signaling crosstalk and translational therapeutics.Signal transduction and targeted therapy · 2026Review
- Statin Use and Arterial Calcification in the General Population: A Longitudinal Analysis and a Negative Control Population.Clinical drug investigation · 2026Article
- Screening for candidate genes and cell populations associated with atherosclerotic calcification using single-cell RNA sequencing.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- The Statin Floor Effect: a Mechanistic Framework for Residual Cardiovascular Risk.Cardiovascular drugs and therapy · 2026Review
- Mechanisms of vascular calcification: cellular phenotype switching drives matrix remodeling and mineralized microenvironment formation.Frontiers in cardiovascular medicine · 2026Review
- Association between Statin use and Abdominal Aortic Calcification in Male, Non-diabetic Elderly.Current vascular pharmacology · 2026Article
- Impact of statins on progression of coronary artery calcium composition and density as assessed by noncontrast CT.The international journal of cardiovascular imaging · 2025Article
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- Icariin inhibits proliferation and migration of VSMCs via LncRNA H19 competitively binding to HuR.Scientific reports · 2025Article
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- Activation of integrin signaling up-regulates pro-inflammatory cytokines in JAK2-V617F positive hematopoietic cells.Cell communication and signaling : CCS · 2025Article
- Protein prenylation in islet β-cell function in health and metabolic stress.Biochemical pharmacology · 2025Review
- Mineral Stress Drives Loss of Heterochromatin: An Early Harbinger of Vascular Inflammaging and Calcification.Circulation research · 2025Article
- IL-1β-driven NF-κB transcription of ACE2 as a Mechanism of Macrophage Infection by SARS-CoV-2.bioRxiv : the preprint server for biology · 2025Article
- The role of macrophages in vascular calcification: strategies for diagnosis and treatment.Frontiers in immunology · 2025Review
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- Understanding Vascular Calcification in Chronic Kidney Disease: Pathogenesis and Therapeutic Implications.International journal of molecular sciences · 2024Review
- Gla Rich Protein (GRP) Mediates Vascular Smooth Muscle Cell (VSMC) Osteogenic Differentiation, Extracellular Vesicle (EV) Calcification Propensity, and Immunomodulatory Properties.International journal of molecular sciences · 2024Article
Corrections and comments
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
Abstract
objectiveCalcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1β (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1β mRNA, and increased Rac1-dependent IL-1β protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1β expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2).
conclusionsStatins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1β signaling axis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.