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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Gan, Wenqiang¹  Ren, Jingyuan²  Li, Tiegang¹  Lv, Silin¹  Li, Chenghe¹  Liu, Ziliang¹  Yang, Min¹ 

[1] Chinese Acad Med Sci, Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

[2] Capital Med Univ, Beijing Anzhen Hosp, Dept Hypertens, Beijing 100029, Peoples R China

关键词: Hypertension;    Cardiac fibrosis;    Serum-glucocorticoid regulated kinase 1;    Inflammation;    NLRP3 inflammasome;   

DOI  :  10.1016/j.bbadis.2017.10.001

来源: Elsevier

【 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)-1 beta 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-1 beta secretion in macrophages by blocking NLRP3 inflammasome activation. By reducing IL-1 beta 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-1 beta. Administration of the NLRP3 inflammasome inhibitor MCC950 indicated that EMD638683 attenuated Ang II-induced cardiac inflammation and fibrosis by inhibiting the NLRP3 inflammasome/IL-1 beta 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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