1. Academic Validation
  2. The SGK1 inhibitor EMD638683, prevents Angiotensin II-induced cardiac inflammation and fibrosis by blocking NLRP3 inflammasome activation

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

  • Biochim Biophys Acta Mol Basis Dis. 2018 Jan;1864(1):1-10. doi: 10.1016/j.bbadis.2017.10.001.
Wenqiang Gan 1 Jingyuan Ren 2 Tiegang Li 1 Silin Lv 1 Chenghe Li 1 Ziliang Liu 1 Min Yang 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 2 Department of Hypertension, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
  • 3 State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050, China. Electronic address: [email protected].
Abstract

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.

Keywords

Cardiac fibrosis; Hypertension; Inflammation; NLRP3 inflammasome; Serum-glucocorticoid regulated kinase 1.

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