Estrogen receptor beta signals to inhibition of cardiac fibrosis

• ERβ activated AMP kinase and PKA block AngII-inhibition of Rho and activation of Rho kinase.
• Loss of Rho/Rho kinase markedly decreased TGFβ and CTGF and myofibroblast formation.
• ERβ signaling diminished MMP and collagens I and III production.
• Many of these aspects were confirmed in an in-vivo model of cardiac hypertrophy.

Cardiac fibrosis evolves from the cardiac hypertrophic state. In this respect, estrogen and estrogen receptor beta (ERβ) inhibit the effects of cardiac hypertrophic peptides that also stimulate fibrosis. Here we determine details of the anti-fibrotic functions of ERβ. In acutely isolated rat cardiac fibroblasts. E2 or a specific ERβ agonist (βLGND2) blocked angiotensin II (AngII) signaling to fibrosis. This resulted from ERβ 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 ERβ signaling resulted in marked decrease of TGFβ 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 βLGND2-treated mice that underwent AngII-induced cardiac hypertrophy. Thus, ERβ in cardiac fibroblasts prevents key aspects of cardiac fibrosis development.