| First Author | Ceneri N | Year | 2017 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 37 |
| Issue | 2 | Pages | 328-340 |
| PubMed ID | 27834690 | Mgi Jnum | J:283006 |
| Mgi Id | MGI:6162317 | Doi | 10.1161/ATVBAHA.116.308507 |
| Citation | Ceneri N, et al. (2017) Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1beta Production. Arterioscler Thromb Vasc Biol 37(2):328-340 |
| abstractText | 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-1beta (IL-1beta) 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-1beta expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1beta levels. Moreover, we found that elevated IL-1beta 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-1beta expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis. |
