Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 37; no. 2; pp. 328 - 340
• Main Authors: Ceneri, Nicolle, Zhao, Lina, Young, Bryan D., Healy, Abigail, Coskun, Suleyman, Vasavada, Hema, Yarovinsky, Timur O., Ike, Kenneth, Pardi, Ruggero, Qin, Lingfen, Qin, Li, Tellides, George, Hirschi, Karen, Meadows, Judith, Soufer, Robert, Chun, Hyung J., Sadeghi, Mehran, Bender, Jeffrey R., Morrison, Alan R.
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.02.2017
• Subjects: Animals; Aorta - enzymology; Aorta - pathology; Aortic Diseases - enzymology; Aortic Diseases - genetics; Aortic Diseases - pathology; Aortic Diseases - prevention & control; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Cells, Cultured; Coronary Artery Disease - enzymology; Coronary Artery Disease - mortality; Coronary Artery Disease - pathology; Coronary Vessels - enzymology; Coronary Vessels - pathology; Female; Genetic Predisposition to Disease; Humans; Inflammation Mediators - metabolism; Interleukin 1 Receptor Antagonist Protein - pharmacology; Interleukin-1beta - metabolism; Macrophages - enzymology; Macrophages - pathology; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - pathology; Neuropeptides - metabolism; Phenotype; Plaque, Atherosclerotic; Prognosis; rac GTP-Binding Proteins - deficiency; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - metabolism; rac1 GTP-Binding Protein - metabolism; RAC2 GTP-Binding Protein; Signal Transduction; Transfection; Up-Regulation; Vascular Calcification - enzymology; Vascular Calcification - mortality; Vascular Calcification - pathology; atherosclerosis; coronary artery disease; macrophages; inflammation; biomarkers
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.116.308507

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.