Serum-glucocorticoid-regulated kinase 1 contributes to mechanical stretch-induced inflammatory responses in cardiac fibroblasts.

Abstract

Excessive mechanical stretch induces production of proinflammatory mediators in cardiac fibroblasts, which could act as inflammatory supporter cells in heart failure. Accumulation evidence and our previous studies suggest that serum-glucocorticoid-regulated kinase 1 (SGK1) contributes to cardiac remodeling and fibrosis, development of heart failure. However, the role and mechanism of SGK1 in mechanical stretch-induced inflammation of cardiac fibroblasts remain unclear. Here, cardiac fibroblasts isolated from wild-type (WT) and SGK1 knockout (SGK1-/-) mice were stimulated by 18% cyclic stretch, under static condition as the control. The results showed that mechanical stretch increased SGK1 expression and activation in WT cardiac fibroblasts but not its isoform, SGK2 or SGK3 expression. Bio-Plex array revealed hyperstretch could enhance chemokines release in WT cardiac fibroblasts, but SGK1 knockout significantly attenuated chemokines production through blocking activation of nuclear factor-kappa B (NF-κB). Moreover, supernatants from WT cardiac fibroblasts subjected to hyperstretch promoted macrophage migration, enhanced expression of macrophage-derived profibrotic mediators, whereas supernatants from SGK1 deficiency suppressed these effects. Although SGK1 did not directly affect mechanical stretch-induced myofibroblast differentiation, SGK1 activation of cardiac fibroblasts facilitated myofibroblast differentiation through the upregulation of the profibrotic mediators secreted by macrophages. These results suggest that SGK1 may play a critical role in the inflammatory cascade of cardiac fibroblasts triggered by mechanical stretch; SGK1 could be used as a potential target for treatment of cardiac fibrosis and heart failure.