Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification

Abstract

Objective: Calcification 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). Conclusions: Statins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1–IL-1β signaling axis.

Coronary Artery Calcification Under Statin Therapy and Its Effect on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

“…Two included studies reported an inverse association, which is in tune with recent theory that statins stabilize plaques by promoting calcification while lowering LDL cholesterol (1); another two reported no association, which is consistent to previous findings from clinical data (5,35,36). Healy et al (37) in a recent article demonstrated that statins, by inhibiting mevalonate synthesis, inhibited downstream cholesterol synthesis and activated downstream Rac1-IL-1β signaling axis. This activation led to a procalcific effect in animal models.…”

Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice

“…The authors suggest that this is due to increased activation of unprenylated Rac1 (i.e., generation of the GTP-bound form of the GTPase) and that effector interactions involved in innate immunity are enhanced. This would presumably also apply to statins and recent findings confirm that disruption of Rac1 regulation via statins leads to increased atherosclerotic plaque calcification (47). However, these effects would not be induced by the modes of inhibition used in the present study, thus avoiding the potential negative effects of statins.…”

Role of Macrophages in the Progression and Regression of Vascular Calcification

“…Recently, Abigail et al found that although statins have been widely developed as hypolipidemic drugs, they can promote atherosclerotic calcification by relieving the inhibitory effect of RhoGDI (Rho GDP-dissociation inhibitor) on the Rac1-IL-1bsignaling axis in macrophages. Supplementing the isoprenaline precursor can offset the pro-calcified effects of statins to a certain extent (Healy et al, 2020). The increase in calcium deposition caused by statins may be associated with plaque stability.…”