Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production
| Autor: | Bryan D. Young, George Tellides, Lina Zhao, Judith L. Meadows, Ruggero Pardi, Süleyman Coşkun, Timur O. Yarovinsky, Lingfen Qin, Nicolle Ceneri, Abigail Healy, Mehran M. Sadeghi, Kenneth Ike, Karen K. Hirschi, Hyung J. Chun, Robert Soufer, Jeffrey R. Bender, Alan R. Morrison, Hema Vasavada, Li Qin |
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| Přispěvatelé: | Ceneri, Nicolle, Zhao, Lina, Young, Bryan D., Healy, Abigail, Coskun, Suleyman, Vasavada, Hema, Yarovinsky, Timur O., Ike, Kenneth, Pardi, Ruggero, Qin, Lingfen, Qiin, Li, Tellides, George, Hirschi, Karen, Meadows, Judith, Soufer, Robert, Chun, Hyung J., Sadeghi, Mehran M., Bender, Jeffrey R., Morrison, Alan R. |
| Rok vydání: | 2017 |
| Předmět: |
Male
rac1 GTP-Binding Protein 0301 basic medicine Pathology Interleukin-1beta Coronary Artery Disease 030204 cardiovascular system & hematology Muscle Smooth Vascular Coronary artery disease atherosclerosi 0302 clinical medicine Macrophage Aorta Cells Cultured Mice Knockout Prognosis Coronary Vessels Plaque Atherosclerotic Up-Regulation rac GTP-Binding Proteins Rac GTP-Binding Proteins Phenotype medicine.anatomical_structure biomarker Biomarker (medicine) Female Inflammation Mediators medicine.symptom Cardiology and Cardiovascular Medicine coronary artery disease Signal Transduction medicine.medical_specialty Myocytes Smooth Muscle Aortic Diseases chemistry.chemical_element Inflammation macrophage Calcium Biology Transfection 03 medical and health sciences Apolipoproteins E medicine Animals Humans Genetic Predisposition to Disease Vascular Calcification Macrophages Neuropeptides Atherosclerosis medicine.disease Mice Inbred C57BL Coronary arteries Interleukin 1 Receptor Antagonist Protein 030104 developmental biology chemistry inflammation Cancer research Calcification |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 37:328-340 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.116.308507 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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