Abstract 439: Statins Disrupt Rac Regulation Leading to Increased Atherosclerotic Calcification

Abstract

Coronary artery disease caused by atherosclerosis is the leading cause of morbidity and mortality in the world. Calcification of atherosclerotic plaque is predictive of increased cardiovascular events; however, recent studies demonstrate that increased calcium density may be associated with more stable disease. Therapeutic modulation of calcified atherosclerotic plaque composition may have potential to reduce event risk. HMG-CoA reductase inhibitors (statins) reduce the risk of cardiovascular events. Moreover, recent data demonstrate that statin use is associated with increased plaque calcification, yet the underlying mechanisms for this process are not well understood. Our laboratory identified a Rac-dependent pathway that promotes IL1B-driven atherosclerotic calcification. Here, we hypothesize that statins disrupt isoprenylation of Rac1, resulting in increased activation of Rac1 and consequent IL1B expression. Results demonstrated statin-induced loss of Rac1 isoprenylation disrupted a complex between Rac1 and its inhibitor, Rho-GDI, in primary macrophages. This led to increased GTP-bound (activated) Rac1 in a statin dose-dependent manner. This phenomena was rescued by a precursor isoprenyl group for Rac1. Statin-treated primary macrophages expressed higher IL1B mRNA and secreted more IL1B protein in response to inflammasome activation. Small molecule inhibition of Rac1 and Rac1 gene-deletion mitigated this statin-induced effect. ApoE -/- mice placed on high fat diet with statin therapy revealed increased plaque calcification in association with elevated serum IL1B protein. In summary, we have defined a potential mechanism of statin-induced calcification, whereby statins disrupt Rho-GDI-mediated inhibition of Rac1.