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

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.

• Authors: Wenqiang Gan, Jingyuan Ren, Tiegang Li, Silin Lv, Chenghe Li, Ziliang Liu, Min Yang
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1864 Issue 1 Pg. 1-10 (Jan 2018) ISSN: 0925-4439 [Print] Netherlands
• PMID: 28986310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Benzamides
• Cardiotonic Agents
• EMD 638683
• Hydrazines
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Angiotensin II

Topics

• Angiotensin II (pharmacology)
• Animals
• Benzamides (pharmacology)
• Cardiotonic Agents (pharmacology)
• Cells, Cultured
• Cytoprotection (drug effects)
• Fibrosis (prevention & control)
• Heart (drug effects)
• Hydrazines (pharmacology)
• Inflammasomes (drug effects, metabolism)
• Inflammation (prevention & control)
• Mice
• Mice, Inbred C57BL
• Myocarditis (pathology, prevention & control)
• Myocardium (pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)