P496Deletion of bambi abolishes the protective effect of orchiectomy against pressure overload-induced myocardial fibrosis by a mechanism involving b-catenin and androgen receptors

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Abstract

Purpose

Pressure overload induces myocardial up-regulation of TGF-b, fibrosis and hemodynamic dysfunction. This remodeling response is prevented by castration in male mice. Bambi is a TGF-β antagonist which acts also as a regulator of the b-catenin pathway. B-catenin is a cofactor of the androgen receptor (AR) and can augment AR signaling. Here, we explored the existence of a cross-talk between Bambi, b-catenin and AR involved in the protective effect of orchiectomy against myocardial fibrosis.

Methods

Wild type (WT) and Bambi KO male mice were subjected to pressure overload by transverse aortic constriction (TAC) for two weeks. A series of mice were castrated (CAST) two months before TAC. 3T3 fibroblasts were transfected with BAMBI-bluescript, siBambi or siAR. To induce b-catenin overexpression, cells were cultured in presence of a GSK3 inhibitor (AR-A014418). We determined the mRNA and protein levels of remodeling-related elements by quantitative PCR or Western Blot.

Results

In WT mice, the myocardial remodeling response to TAC was prevented by castration. Bambi deletion completely abolishes the protective effect of orchiectomy against myocardial fibrosis and hemodynamic deterioration induced by TAC. CAST + TAC-KO compared with CAST + TAC-WT mice showed myocardial overexpression of TGF-b (11 ± 2.6 vs 0.9 ± 0.2, p < 0.001), collagen I (123 ± 20 vs 58 ± 15; p < 0.001), b-catenin (7.4 ± 0.2 vs 3.1 ± 0.2; p < 0.001) and androgen receptors (AR) (0.2 ± 0.04 vs 0.1 ± 0.02, p < 0.05). The expression levels of TGF-b, b-catenin and AR were significantly and directly correlated with each other. In cultured fibroblasts both activation of AR with dihydrotestosterone (10nM DHT) and increasing b-catenin levels with AR-A014418 induced TGF-b up-regulation (4.6 fold). In the absence of androgenic effects, siBambi potentiated (i) the translocation of b-catenin to the nucleus and (ii) TGF-b up-regulation (control 60.7 ± 3.6 vs siBAMBI 98.1 ± 5.1; p < 0.001); both effects were inhibited by silencing the AR.

Conclusion

Orchiectomy prevented the pathological myocardial remodeling under pressure overload, while Bambi deletion conferred to male KO mice resistance to castration. The results in cultured fibroblasts suggest that the transcription of TGF-b was modulated by androgens interacting with AR. On the other hand, silencing Bambi would promote TGF-b overexpression in the absence of androgens through the interaction of b-catenin with AR. This mechanism would explain the lack of sensitivity to gonadectomy displayed by KO mice. (Funding: ISCIII, PS09/01097; FMV-UC 09/01; FMV-API 10/20).

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