Mechanism of the inhibitory effect of atorvastatin on endoglin expression induced by transforming growth factor-beta1 in cultured cardiac fibroblasts.

AIMS: Transforming growth factor-beta1 (TGF-beta1) and endoglin play a causal role in promoting cardiac fibrosis. Atorvastatin has been shown to have an inhibitory effect on cardiac fibroblasts in vitro. However, the effects of statins on TGF-beta1 and endoglin are poorly understood. We therefore sought to investigate the molecular mechanisms of atorvastatin on endoglin expression after TGF-beta1 stimulation in cardiac fibroblasts. METHODS AND
RESULTS: Cultured cardiac fibroblasts were obtained from adult male Sprague-Dawley rat hearts. TGF-beta1 stimulation increased endoglin and collagen I expression and atorvastatin inhibited the induction of endoglin and collagen I by TGF-beta1. Phosphatidylinositol-3 kinase (PI-3) and Akt inhibitors (wortmannin and Akt inhibitor X) completely attenuated the endoglin protein expression induced by TGF-beta1. TGF-beta1 induced phosphorylation of PI-3 kinase and Akt, while atorvastatin and wortmannin and Akt inhibitor X inhibited the phosphorylation of PI-3 kinase and Akt induced by TGF-beta1. The gel shift and promoter activity assay showed that TGF-beta1 increased Smad3/4-binding activity and endoglin promoter activity, while wortmannin and atorvastatin inhibited the Smad3/4-binding activity and endoglin promoter activity induced by TGF-beta1. TGF-beta1 increased collagen I protein expression, while endoglin siRNA attenuated collagen I protein expression induced by TGF-beta1. Atorvastatin decreased left ventricular TGF-beta1, endoglin, and collagen I protein expression and fibrotic area in a rat model of volume overload heart failure.
CONCLUSION: Atorvastatin inhibits endoglin expression through the inhibition of PI-3 kinase, Akt, and Smad3 phosphorylation, and reduced Smad3/4 binding activity and endoglin promoter activity in cardiac fibroblasts.