| First Author | Lavall D | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 18 | Pages | 7542-7553 |
| PubMed ID | 28320863 | Mgi Jnum | J:242497 |
| Mgi Id | MGI:5905499 | Doi | 10.1074/jbc.M116.764449 |
| Citation | Lavall D, et al. (2017) Rac1 GTPase regulates 11beta hydroxysteroid dehydrogenase type 2 and fibrotic remodeling. J Biol Chem 292(18):7542-7553 |
| abstractText | The aim of the study was to characterize the role of Rac1 GTPase for the mineralocorticoid receptor (MR)-mediated pro-fibrotic remodeling. Transgenic mice with cardiac overexpression of constitutively active Rac1 (RacET) develop an age-dependent phenotype with atrial dilatation, fibrosis, and atrial fibrillation. Expression of MR was similar in RacET and WT mice. The expression of 11beta hydroxysteroid dehydrogenase type 2 (11beta-HSD2) was age-dependently up-regulated in the atria and the left ventricles of RacET mice on mRNA and protein levels. Statin treatment inhibiting Rac1 geranylgeranylation reduced 11beta-HSD2 up-regulation. Samples of human left atrial myocardium showed a positive correlation between Rac1 activity and 11beta-HSD2 expression (r = 0.7169). Immunoprecipitation showed enhanced Rac1-bound 11beta-HSD2 relative to Rac1 expression in RacET mice that was diminished with statin treatment. Both basal and phorbol 12-myristate 13-acetate (PMA)-induced NADPH oxidase activity were increased in RacET and correlated positively with 11beta-HSD2 expression (r = 0.788 and r = 0.843, respectively). In cultured H9c2 cardiomyocytes, Rac1 activation with l-buthionine sulfoximine increased; Rac1 inhibition with NSC23766 decreased 11beta-HSD2 mRNA and protein expression. Connective tissue growth factor (CTGF) up-regulation induced by aldosterone was prevented with NSC23766. Cardiomyocyte transfection with 11beta-HSD2 siRNA abolished the aldosterone-induced CTGF up-regulation. Aldosterone-stimulated MR nuclear translocation was blocked by the 11beta-HSD2 inhibitor carbenoxolone. In cardiac fibroblasts, nuclear MR translocation induced by aldosterone was inhibited with NSC23766 and spironolactone. NSC23766 prevented the aldosterone-induced proliferation and migration of cardiac fibroblasts and the up-regulation of CTGF and fibronectin. In conclusion, Rac1 GTPase regulates 11beta-HSD2 expression, MR activation, and MR-mediated pro-fibrotic signaling. |
