Androgen attenuates cardiac fibroblasts activations through modulations of transforming growth factor-β and angiotensin II signaling

Background Androgen deficiency produces heart failure, which can be ameliorated by testosterone supplementation. Cardiac fibrosis plays a critical role in the pathophysiology of heart failure. This study aimed to evaluate whether testosterone can attenuate cardiac fibroblast activity through modulating transforming growth factor (TGF)-β and angiotensin (Ang) II signaling. Methods Migration, proliferation, myofibroblast differentiation, collagen production, and transcription signaling were evaluated in adult male rat (weighing 300–350 g) cardiac fibroblasts with and without incubation with testosterone (10 nM) and co-administration of TGF-β1 (10 ng/ml) or Ang II (100 nM) by cell migration analysis, proliferation assay, soluble collagen measurement, zymographic analysis, immunofluorescence microscopy, real-time PCR and Western blot. Results Compared to those without testosterone, testosterone-treated fibroblasts exhibited less collagen production. Testosterone-treated fibroblasts also had less migration, proliferation, myofibroblast differentiation, and collagen production in the presence of TGF-β1, or had less collagen production with Ang II. Testosterone-treated fibroblasts had decreased phosphorylated Akt, mammalian target of rapamycin, and 4E binding protein-1 irrespective of TGF-β1 treatment and had increased matrix metalloproteinase (MMP)-2 in the presence of TGF-β1 treatment, and had decreased phosphorylated P38 and Smad 2/3 levels in the presence of Ang II. Cardiac fibroblasts with and without testosterone had similar mRNA and protein expressions of total Akt and total Smad 2/3 irrespective of TGF-β1 or Ang II treatment. Conclusion Physiological level of testosterone attenuated Akt and Smad 2/3 phosphorylation mediated by TGF-β1 and angiotensin II respectively, which can result in decreased cardiac fibroblast activation and potentially contribute to beneficial effects in heart failure.