Estrogen receptor beta signals to inhibition of cardiac fibrosis

Cardiac fibrosis evolves from the cardiac hypertrophic state. In this respect, estrogen and estrogen receptor beta (ER beta) inhibit the effects of cardiac hypertrophic peptides that also stimulate fibrosis. Here we determine details of the anti-fibrotic functions of ER beta. In acutely isolated rat cardiac fibroblasts. E2 or a specific ER beta agonist ((beta LGND2) blocked angiotensin II (AngII) signaling to fibrosis. This resulted from ER beta activating protein kinase A and AMP kinase, inhibiting both AngII de-phosphorylation of RhoA and the resulting stimulation of Rho kinase. Inhibition of Rho kinase from ER beta signaling resulted in marked decrease of TGF beta expression, connective tissue growth factor production and function, matrix metalloproteinases 2 and 9 expression and activity, and the conversion of fibroblasts to myofibroblasts. Production of collagens I and III were also significantly decreased. Several important aspects were corroborated in-vivo from beta LGND2-treated mice that underwent AngII-induced cardiac hypertrophy. Thus, ER beta in cardiac fibroblasts prevents key aspects of cardiac fibrosis development. Published by Elsevier Ireland Ltd.