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Abstract Number: 877

Sildenafil Attenuates the Fibrotic Phenotype in Scleroderma Skin Fibroblasts

Tomoaki Higuchi1, Yasushi Kawaguchi1, Kae Takagi1, Akiko Tochimoto1, Yuko Ota2, Yasuhiro Katsumata1, Takahisa Gono1, Masanori Hanaoka1, Yuko Okamoto1, Hidenaga Kawasumi1 and Hisashi Yamanaka3, 1Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, 210-22 Kawada-Cha Shinjuku-Ku, Tokyo Women's Medical University, Tokyo, Japan, 3Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, fibrosis, scleroderma and systemic sclerosis

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Clinical Aspects and Therapeutics I: Systemic Sclerosis, Advances in Therapy

Session Type: Abstract Submissions (ACR)

Background/Purpose

Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation, vasculopathy and fibrosis. Tissue fibrosis directly contributes to mortality or quality of life. However, the effective therapy has not been established. Aberrantly activated fibroblasts in the affected area of SSc, which play a main role in the production and remodeling of collagen and other extracellular matrix components, is thought to be a key therapeutic target. Recent researches showed that stimulation of soluble guanylate cyclase (sGC) reverted fibrotic phenotype of SSc and other fibrotic disorders in vivo and in vitro by increasing levels of intracellular cyclic GMP (cGMP). The purpose of the present study is to assess the anti-fibrotic properties of cGMP in cultured fibroblasts from patients with SSc. 

Methods

Skin fibroblasts were obtained from patients with diffuse cutaneous SSc. Intracellular cGMP levels were measured using a commercially available ELISA kit. To increase the intracellular concentration of cGMP, sildenafil, an inhibitor of phosphodiesterase (PDE) 5, was added. Expression of PDE5 and alpha smooth muscle actin (αSMA) were analyzed by immunohistochemistry. Gene expressions related to profibrotic marker were evaluated by quantitative RT-PCR. Western blotting and ELISA were performed to investigate the effects of sildenafil on the downstream pathway of TGF-β. 

Results

PDE5 expression on skin fibroblasts was confirmed by immunohistochemistry. Baseline cGMP levels in SSc skin fibroblasts were significantly higher than those in healthy skin fibroblasts.  Sildenafil increased cGMP levels in a dose dependent manner in skin fibroblasts, and then our results indicated that sildenafil significantly decreased the expression of profibrotic genes, which were augmented by TGF-β1, including COL1A1, COL1A2, CTGF and ACTA2 in SSc skin fibroblasts. Conversely, these inhibitory effects of sildenafil were found to be weak in healthy skin fibroblasts. Also, we confirmed using immunohistochemistry that the protein levels of αSMA in SSc skin fibroblasts were down-regulated by sildenafil. Next, we explored the effects of sildenafil on the signal pathway of TGF-β. Sildenafil significantly reduced phosphorylation of p38 induced by TGF-β1, but did not affect phosphorylation of Smad3. In addition, sildenafil reduced Rho kinase activity.

Conclusion

We demonstrated that sildenafil attenuated the fibrotic phenotype of SSc skin fibroblasts induced by TGF-β1. This effect may be attributed by non-Smad signaling pathways, including MAPK and Rho kinase cascade. Sildenafil has been used for the treatment of SSc -associated pulmonary arterial hypertension and Raynaud phenomenon by its potent vasodilating effect. In addition, our findings would provide the evidence that sildenafil may have the potential to improve fibrotic lesions in SSc.


Disclosure:

T. Higuchi,
None;

Y. Kawaguchi,
None;

K. Takagi,
None;

A. Tochimoto,
None;

Y. Ota,
None;

Y. Katsumata,
None;

T. Gono,
None;

M. Hanaoka,
None;

Y. Okamoto,
None;

H. Kawasumi,
None;

H. Yamanaka,
None.

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