Inhibitory regulation of apelin on fibrosis in systemic sclerosis

Abstract

The secreted protein apelin and its receptor APJ signaling mainly regulates angiogenesis and cardiovascular functions. Recently, it has been identified that apelin: APJ signaling also regulates cardiac and arterial fibrosis. However, the mechanisms and roles of apelin in skin fibrosis in systemic sclerosis (SSc) are not well characterized. The aim of this study was to elucidate the role of apelin in skin fibrosis in SSc. We first demonstrated that the plasma apelin levels were negatively correlated with modified Rodnan total skin score in SSc patients. Expression of apelin in SSc fibroblasts was significantly lower than that in normal fibroblasts. In addition, decreased apelin synthesis in fibroblasts was induced by stimulation with TGF-β, suggesting that the activation of TGF-β signaling in SSc might be responsible for the reduced apelin expression in SSc fibroblasts. siRNA depletion of apelin from fibroblasts significantly enhanced collagen type I, αSMA and sphingosine kinase 1 (SPHK1) expressions. Furthermore, treatment with apelin protein significantly inhibited TGF-β-induced overexpression of collagen type I, αSMA and SPHK1 in fibroblasts. These results suggest that apelin might have an inhibitory action against TGF-β-induced skin fibrosis. Finally, we demonstrated that administration of apelin significantly inhibited bleomycin-induced dermal fibrosis in mice. Collectively, TGF-β signaling and apelin signaling may counteract each other in the fibrotic process of SSc. Apelin signaling may be involved in the pathogenesis of SSc, and have therapeutic potential for fibrosis in SSc.