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Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production
Open accessAbstract
Objective—: The calcium composition of atherosclerotic plaque is thought to be associated with increased risk for cardiovascular events, but whether plaque calcium itself is predictive of worsening clinical outcomes remains highly controversial. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Approach and Results—: Here, we identify Rac2 as a major inflammatory regulator of signaling that directs plaque osteogenesis. In experimental atherogenesis, Rac2 prevented progressive calcification through its suppression of Rac1-dependent macrophage interleukin-1β (IL-1β) expression, which in turn is a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs. Calcified coronary arteries from patients revealed decreased Rac2 expression but increased IL-1β expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1β levels. Moreover, we found that elevated IL-1β was an independent predictor of cardiovascular death in those subjects with high coronary calcium burden. Conclusions—: Overall, these studies identify a novel Rac2-mediated regulation of macrophage IL-1β expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.
Overview
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TL;DR
Rac2 suppresses macrophage IL-1β production by limiting Rac1 activity, and loss of Rac2 promotes atherosclerotic calcification in mice. In humans, calcified coronary plaque has lower Rac2 and higher IL-1β, and elevated serum IL-1β predicts cardiovascular death in patients with high coronary calcium burden.
Key findings
- In ApoE−/− mice on high-fat diet, aortic calcification rose modestly to 14 weeks then dramatically between 14 and 21 weeks; Rac2 expression initially tracked macrophage influx but fell at 21 weeks despite sustained F4/80, while IL-1β increased significantly between 14 and 21 weeks.
- Human calcified coronary segments had significantly reduced Rac2 mRNA and increased IL-1β expression, with unchanged Rac1 and CSF1R; Rac2−/−ApoE−/− mice showed increased macrocalcification, osteogenic genes RUNX2/SOX9/OSX/MSX2, and ALP.
- Bone marrow transplantation showed the calcification phenotype tracked with hematopoietic Rac2: Rac2−/− marrow into Rac2+/+ recipients increased calcification, while Rac2+/+ marrow into Rac2−/− recipients decreased it; serum IL-1β was elevated in mice receiving Rac2−/− marrow.
- In human stable CAD, serum IL-1β correlated with CACS; high calcium burden had HR 4.88 (95% CI 1.03–22.98, P=0.045) for cardiovascular events (10 total: 6 sudden cardiac deaths, 1 STEMI, 2 NSTEMI, 1 ACS), and all events occurred in subjects with IL-1β >1.8 pg/ml.
Methods
- Mouse studies used ApoE−/− and Rac2−/−ApoE−/− mice on high-fat diet, with near-infrared bisphosphonate imaging, microCT, histology, RNA/protein analyses, bone marrow transplantation, BMDMs, MASMCs, and IL-1ra treatment.
- Human studies analyzed coronary segments from explanted hearts of patients undergoing orthotopic heart transplant for ischemic cardiomyopathy, classified as calcified vs noncalcified by noncontrast CT Agatston criteria and EVG staining; a separate chronic stable CAD cohort had serum IL-1β measured and coronary artery calcium scoring by non-ECG-gated non-contrast chest CT.
- Main analyses compared expression/calcification between groups, tested IL-1β signaling dependence with inhibitors/genetic deletion, and assessed clinical associations/outcomes including hazard ratio.
Limitations
- The paper states the human clinical analysis requires further study because the sample size is small and the analysis is retrospective.
- Evident from the text: mechanistic cause-effect conclusions rely heavily on mouse models and cell culture, while human data are associative; the human coronary expression analysis uses explanted hearts from transplant patients, which may not represent broader CAD populations.
- Methods details are in the online-only Data Supplement, so the main text alone does not allow full assessment of experimental procedures.
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In the paper
“Of note, IL-1β expression was found to be significantly increased in the coronary artery segments containing calcified plaque in a manner consistent with the animal model (Fig. 1J).”
§ Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage IL-1β Production > Results > Calcified plaque is associated with increased IL-1β and decreased Rac2 expression
plainstates an association- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rac2−/−ApoE−/− aortas contained additional areas of hyperattenuation indicative of macrocalcification along the lesser curvature of the aortic arch (Fig. 2A, upper panels, yellow arrows), which was further confirmed by quantification of Alizarin Red staining (Fig. 2A, lower panels, and 2B).”
§ Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage IL-1β Production > Results > Rac2 deletion leads to increased plaque calcification
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“Hematoxylin and eosin staining of aortic sinus plaque and quantification of plaque area revealed similar plaque burden in Rac2+/+ApoE−/− and Rac2−/−ApoE−/− mice (Fig. ID,E).”
§ Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage IL-1β Production > Results > Rac2 deletion does not affect serum cholesterol or plaque lipid composition
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“elevated IL-1β was an independent predictor of cardiovascular death in those subjects with high coronary calcium burden.”
§ Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage IL-1β Production > Abstract > Approach and Results
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“In experimental atherogenesis, Rac2 prevented progressive calcification through its suppression of Rac1-dependent macrophage IL-1β expression”
- Also stated in: § Rac2 deletion leads to increased plaque calcification · plain
“Rac2−/−ApoE−/− aortas from mice on HFD for 14 weeks revealed significant increases in relative calcification over mice fed normal chow or control mice on a HFD.”
§ Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage IL-1β Production > Abstract > Approach and Results
plainstates a cause- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Rac2 deletion leads to increased plaque calcification · plain
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Citations
Cites
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From Vulnerable Plaque to Vulnerable Patient
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From Vulnerable Plaque to Vulnerable Patient
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Cited by
Durham, A. L., Speer, M. Y., Scatena, M., Giachelli, C. M., & Shanahan, C. M. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy010 · Cited by 1,172
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Vascular Calcification—New Insights into Its Mechanism
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Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets
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Aortic Valve Stenosis: From Basic Mechanisms to Novel Therapeutic Targets
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Metadata
- Authors
- Ceneri, N., Zhao, L., Young, B. D., Healy, A., Coskun, S., Vasavada, H., Yarovinsky, T. O., Ike, K., Pardi, R., Qin, L., Qin, L., Tellides, G., Hirschi, K., Meadows, J., Soufer, R., Chun, H. J., Sadeghi, M. M., Bender, J. R., & Morrison, A. R.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- From the Department of Internal Medicine (Section of Cardiovascular Medicine), VA Connecticut Healthcare System, West Haven (N.C., L.Z., A.H., L.Q., G.T., J.M., R.S., M.M.S., A.R.M.); Department of Medicine and Division of Cardiology, Providence VA Medical Center, RI (A.H., A.R.M.); Department of Internal Medicine (Section of Cardiovascular Medicine), Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (N.C., L.Z., B.D.Y., A.H., S.C., H.V., T.O.Y., K.I., L.Q., L.Q....
- Corresponding author
- Ceneri, Nicolle
- Zhao, Lina
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2017-02
- Volume
- 37
- Issue
- 2
- Pages
- 328-340
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC5269510
- OpenAlex
- W2551261660
- Cited by
- 124
- References
- 54
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 15 · 2023: 18 · 2022: 16 · 2021: 14 · 2020: 17 · 2019: 14 · 2018: 8 · 2017: 4
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (IK2BX002527)
- Swedish Orphan Biovitrum
- National Institutes of Health (UL1TR001863)
- National Heart, Lung, and Blood Institute (R01HL043331, R01HL113005, L30 HL115713, F32HL097422, R01HL128064, T32HL007950)
- National Cancer Institute (P30CA016359)
- National Institute of General Medical Sciences (P20GM103652)
- National Institute of Biomedical Imaging and Bioengineering (R01EB016629, UH3EB017103)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiac Imaging and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- Rac2, atherosclerotic calcification, vascular calcification, IL-1β, macrophages, Rac1, vascular smooth muscle cells, coronary artery disease, cardiovascular mortality, inflammation, biomarkers, therapeutic target
- MeSH terms
- RAC2 GTP-Binding Protein, Animals, Aorta, Aortic Diseases, Apolipoproteins E, Cells, Cultured, Coronary Artery Disease, Coronary Vessels, Female, Humans, Macrophages, Male, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Neuropeptides, Phenotype, Prognosis, Transfection, Signal Transduction, Up-Regulation, Mice, Knockout, Inflammation Mediators, Genetic Predisposition to Disease, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, Myocytes, Smooth Muscle, Atherosclerosis, Interleukin-1beta, Interleukin 1 Receptor Antagonist Protein, Plaque, Atherosclerotic, Vascular Calcification
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- Ceneri, N., Zhao, L., Young, B. D., Healy, A., Coskun, S., Vasavada, H., Yarovinsky, T. O., Ike, K., Pardi, R., Qin, L., Qin, L., Tellides, G., Hirschi, K., Meadows, J., Soufer, R., Chun, H. J., Sadeghi, M. M., Bender, J. R., & Morrison, A. R. (2017). Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production. Arteriosclerosis, Thrombosis, and Vascular Biology. https://doi.org/10.1161/atvbaha.116.308507
