Rac1-Mediated Effects of HMG-CoA Reductase Inhibitors (Statins) in Cardiovascular Disease

Abstract

HMG-CoA reductase inhibitors (statins) lower serum cholesterol concentrations and are beneficial in the primary and secondary prevention of coronary heart disease. The positive clinical effects have only partially been reproduced with other lipid-lowering interventions suggesting potential statin effects in addition to cholesterol lowering. In experimental models, direct beneficial cardiovascular effects that are mediated by the inhibition of isoprenoids have been documented, which serve as lipid attachments for intracellular signaling molecules such as small Rho guanosine triphosphate-binding proteins, whose membrane localization and function are dependent on isoprenylation. Rac1 GTPase is an established master regulator of cell motility through the cortical actin reorganization and of reactive oxygen species generation through the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Observations in cells, animals, and humans have implicated the activation of Rac1 GTPase as a key component of cardiovascular pathologies, including the endothelial dysfunction, cardiac hypertrophy and fibrosis, atrial fibrillation, stroke, hypertension, and chronic kidney disease. However, the underlying signal transduction remains incompletely understood. Based on the recent advance made in Rac1 research in the cardiovascular system by using mouse models with transgenic overexpression of activated Rac1 or conditional knockout, as well as Rac1-specific small molecule inhibitor NSC 23766, the improved understanding of the Rac1-mediated effects statins may help to identify novel therapeutic targets and strategies.