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The SGK1 inhibitor EMD638683, prevents Angiotensin Ⅱ–induced cardiac inflammation and fibrosis by blocking NLRP3 inflammasome activation

GAN-Wenqiang  REN-Jingyuan  LI-Tiegang  LV-Silin  LI-Chenghe  LIU-Ziliang  YANG-Min  
【摘要】:Inflammation has emerged as a critical biological process contributing to hypertensive cardiac remodeling. Effective pharmacological treatments targeting the cardiac inflammatory response, however, are still lacking. Prior studies suggested that the serum-and glucocorticoid-inducible kinase(SGK1) plays a key role in inflammation and cardiac remodeling. Recently, a highly selective SGK1 inhibitor, EMD638683, was developed, though whether EMD638683 can prevent hypertension-induced cardiac fibrosis and the mechanisms by which this inhibitor may alter the disease process remain unknown. Using a murine Angiotension Ⅱ(Ang Ⅱ) infusion-induced hypertension model we found that EMD638683 treatment inhibited cardiac fibrosis and remodeling, with significant abatement of cardiac inflammation. EMD638683 was shown to suppress Ang Ⅱ infusion-induced interleukin(IL)-1β release, and substantially reduce nucleotide-binding oligomerization domain-like receptor with pyrin domain 3(NLRP3) expression and caspase-1 activation in cardiac tissues. In vitro experiments revealed that EMD638683 ameliorated Ang Ⅱ stimulated IL-1β secretion in macrophages by blocking NLRP3 inflammasome activation. By reducing IL-1β 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-1β. Administration of the NLRP3 inflammasome inhibitor MCC950 indicated that EMD638683 attenuated Ang Ⅱ-induced cardiac inflammation and fibrosis by inhibiting the NLRP3 inflammasome/IL-1β secretion axis. These findings indicate that the SGK1 inhibitor EMD638683 can negatively regulate NLRP3 inflammasome activation, and may represent a promising approach to the treatment of hypertensive cardiac damage.

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