Sildenafil attenuates the fibrotic phenotype of skin fibroblasts in patients with systemic sclerosis

- Intracellular cGMP levels were higher in skin fibroblasts obtained from patients with systemic sclerosis (SSc) compared to the levels from healthy skin fibroblasts.
- Sildenafil reduced the expression of type I collagen, CTGF and αSMA in SSc skin fibroblasts stimulated by TGF-β1.
- The anti-fibrotic effects of sildenafil were dependent on non-canonical TGF-β signaling.

Systemic sclerosis (SSc) is a multi-organ fibrotic disease that affects the skin and various internal organs. Therapeutic strategies for tissue fibrosis have not been established; however, aberrantly activated fibroblasts in affected lesions are key targets for modulating fibrosis. Recently, increased intracellular cyclic GMP (cGMP) levels were demonstrated to improve fibrosis levels in various diseases. The purpose of this study was to assess the anti-fibrotic properties of cGMP in cultured fibroblasts from patients with SSc. The phosphodiesterase (PDE) 5 inhibitor sildenafil increased the intracellular cGMP levels in skin fibroblasts in a dose-dependent manner. Sildenafil treatment also significantly decreased the expression of several pro-fibrotic factors that were upregulated by TGF-β1 treatment in SSc skin fibroblasts. These inhibitory effects occurred via non-canonical TGF-β signaling. Our findings revealed that sildenafil might be a novel strategy to treat tissue fibrosis and vasculopathy in SSc.