Markus Waldeck-Weiermair, DMSc
Markus Waldeck-Weiermair, Shambhu Yadav, Jonas Kaynert, Venkata Revanth Thulabandu, Arvind Pandey, Fotios Spyropoulos, Taylor Covington, Christina Krüger, and Thomas Michel
Research Category: Cardiovascular, Diabetes, and Metabolic Disorders
Statins are HMG-CoA reductase inhibitors that are widely used to treat cardiovascular disease. In addition to cholesterol-lowering effects, statins are associated with antioxidant effects that lead to beneficial cardiovascular outcomes. We used live-cell imaging approaches exploiting the hydrogen peroxide (H2O2) biosensor HyPer7 to probe the mechanisms whereby statins modulate redox balance in endothelial cells. We found that the small GTPase Rac1 is a critical determinant of H2O2-mediated responses, and discovered that statins promote Rac1 translocation via inhibition of Rac1 prenylation. We found that NADPH oxidase isoforms Nox2 and Nox4 differentially modulate receptor-dependent H2O2 responses. These studies indicate that the salutary effects of statins may be explained in part by statin-dependent inhibition of the Rac1/Nox axis, thereby attenuating endothelial oxidative stress.
Statins have manifold protective effects on the cardiovascular system. In addition to lowering LDL cholesterol levels, statins have antioxidant effects involving intracellular redox pathways that are incompletely understood. Inhibition of HMG-CoA reductase by statins also blocks the synthesis of lipids necessary for the post-translational modification of signaling proteins, including the small GTPase Rac1. Here we studied the mechanisms whereby Rac1 and statins modulate the intracellular oxidant hydrogen peroxide (H2O2). Live-cell imaging experiments using the H2O2 biosensor HyPer7 revealed robust H2O2 generation in human umbilical vein endothelial cells following activation of receptors for histamine or vascular endothelial growth factor (VEGF). Both VEGF- and histamine-stimulated H2O2 responses were abrogated by siRNA-mediated Rac1 knockdown. VEGF responses required the NADPH oxidase (Nox) isoforms Nox2 and Nox4, whereas histamine-stimulated H2O2 signals were independent of Nox4 but still required Nox2. Endothelial H2O2 responses to both histamine and VEGF were completely inhibited by simvastatin. Simvastatin treatment promotes Rac1 translocation from cellular membrane to the cell nucleus. These simvastatin effects are rescued by cell treatment with mevalonic acid, the enzymatic product of the HMG-CoA reductase. Taken together, these studies establish that intracellular H2O2 responses to histamine and VEGF involve distinct Nox isoforms, and are completely dependent on Rac1.