SGK1 inhibition as potential anti-inflammatory therapeutics targeting hypertensive cardiac fibrosis

抄録

Background: Inflammation has emerged as a critical biological process contributing to hypertensive cardiac remodeling. Unfortunately, in clinical studies, approaches targeting several specific inflammatory pathways have not yet translated into effective therapy. Thus, selective targeting of injurious proinflammatory signals is needed. The serum and glucocorticoid inducible kinase 1 (SGK1) is a member of the serine-threonine kinase gene family that plays the important roles in various physiological and pathophysiological processes. SGK1 is involved in complex intracellular signaling via inflammatory and oxidative pathways that lead to fibrosis, though whether SGK1 may therefore be a valuable target of pharmacologic approaches to inhibit inflammation and the progression of cardiac fibrosis remain unclear.

Methods and Results: Using a murine Angiotension II (Ang II) infusion induced hypertension model we found that SGK1 knockout in mice significantly attenuated cardiac inflammation and fibrosis after Ang II infusion. This attenuation was associated with inhibition of activation of STAT3 and reduced differentiation to M2 macrophages and profibrotic cytokine expression, thereby leading to decreased fibroblast-to-myofibroblast transition and cardiac fibrosis. Importantly, pharmacological inhibition of SGK1 by EMD638683 prevented Ang II-induced cardiac fibrosis and hypertrophy with significant abatement of cardiac inflammation. EMD638683 was shown to suppress Ang II infusion-induced IL-1beta release, and substantially reduce NLRP3 expression and caspase-1 activation in cardiac tissues. EMD638683 ameliorated Ang II-stimulated IL-1beta secretion in macrophages by blocking NLRP3 inflammasome activation. By reducing IL-1beta production in macrophages, the transformation of fibroblasts to myofibroblasts was inhibited. The effects of EMD638683 on cardiac fibrosis were abolished by supplementation with exogenous IL-1beta. Administration of the NLRP3 inflammasome inhibitor MCC950 indicated that EMD638683 attenuated Ang II-induced cardiac inflammation and fibrosis by inhibiting the NLRP3 inflammasome/IL1-beta secretion axis.

Conclusions: We provide new evidence for a potential molecular mechanism linking SGK1 required for macrophage polarization to the pathogenesis of hypertensive cardiac fibrosis, the SGK1 inhibitor EMD638683 indeed represents a potential anti-inflammatory agent for the treatment of hypertensive cardiac damage, which primarily acts through down regulation of NLRP3 inflammasome activation.