Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption.
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 inhibito...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4712048?pdf=render |
| _version_ | 1818949242715111424 |
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| author | Marsha C Lampi Courtney J Faber John Huynh Francois Bordeleau Matthew R Zanotelli Cynthia A Reinhart-King |
| author_facet | Marsha C Lampi Courtney J Faber John Huynh Francois Bordeleau Matthew R Zanotelli Cynthia A Reinhart-King |
| author_sort | Marsha C Lampi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T08:59:35Z |
| format | Article |
| id | doaj.art-17923a92fb884e909a621d63b453e267 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T08:59:35Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-17923a92fb884e909a621d63b453e2672022-12-21T19:45:53ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01111e014703310.1371/journal.pone.0147033Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption.Marsha C LampiCourtney J FaberJohn HuynhFrancois BordeleauMatthew R ZanotelliCynthia A Reinhart-KingArterial 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.http://europepmc.org/articles/PMC4712048?pdf=render |
| spellingShingle | Marsha C Lampi Courtney J Faber John Huynh Francois Bordeleau Matthew R Zanotelli Cynthia A Reinhart-King Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption. PLoS ONE |
| title | Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption. |
| title_full | Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption. |
| title_fullStr | Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption. |
| title_full_unstemmed | Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption. |
| title_short | Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption. |
| title_sort | simvastatin ameliorates matrix stiffness mediated endothelial monolayer disruption |
| url | http://europepmc.org/articles/PMC4712048?pdf=render |
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