Abstract
Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening.
Highlights
Age is a primary risk factor for atherosclerosis, and vascular stiffness increases with age due to changes in the extracellular matrix which include increased elastin fragmentation, collagen deposition, and collagen cross-linking by advanced glycation end products (AGEs) [1,2,3,4]
To investigate the effect of simvastatin on endothelial barrier disruption associated with elevated RhoA activity caused by increased matrix stiffness, we probed RhoA activity and markers of endothelium integrity in response to both substrate stiffness and simvastatin treatments
We investigated the effect of simvastatin on Rac1 activity, noting that Rac1 is reported to have inverse activation when compared to RhoA, and that Rac1 is altered by simvastatin to improve endothelial barrier function [28,31,39]
Summary
Age is a primary risk factor for atherosclerosis, and vascular stiffness increases with age due to changes in the extracellular matrix which include increased elastin fragmentation, collagen deposition, and collagen cross-linking by advanced glycation end products (AGEs) [1,2,3,4]. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials
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