Dataset Information

Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1? Production.

ABSTRACT: 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-1? (IL-1?) 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-1? expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1? levels. Moreover, we found that elevated IL-1? 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-1? expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.

SUBMITTER: Ceneri N

PROVIDER: S-EPMC5269510 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Ceneri Nicolle N Zhao Lina L Young Bryan D BD Healy Abigail A Coskun Suleyman S Vasavada Hema H Yarovinsky Timur O TO Ike Kenneth K Pardi Ruggero R Qin Lingfen L Qin Li L Tellides George G Hirschi Karen K Meadows Judith J Soufer Robert R Chun Hyung J HJ Sadeghi Mehran M MM Bender Jeffrey R JR Morrison Alan R AR

Arteriosclerosis, thrombosis, and vascular biology 20161110 2

<h4>Objective</h4>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.<h4>Approach and results</h4>Here, we identify Rac2 as a major inflammatory regulator of signaling t ...[more]

PMID: 27834690

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Project description: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.

Dataset Information

Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1? Production.

Publications

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

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