Esaxerenone Blocks Vascular Endothelial Inflammation Through SGK1.

Abstract

ABSTRACT:

Chronic low-grade inflammation and excess mineralocorticoid receptor (MR) activation are well-known pathological conditions of metabolic syndrome (MetS). To elucidate the crosstalk between inflammation and MR signaling, we focused on serum/glucocorticoid-regulated kinase 1 (SGK1) in vascular endothelial cells. We treated human aortic endothelial cells (HAECs) with esaxerenone (ESX), a novel nonsteroidal highly selective MR antagonist, or spironolactone (SPL), a classic competitive MR antagonist, followed by stimulation with tumor necrosis factor (TNF)-α. ESX at therapeutic concentrations attenuated the long-term induction of TNF-α-stimulated inflammatory molecules in HAEC, whereas SPL had only a minor effect at 10 μM. We found long-term TNF-α-stimulated induction of SGK1 mRNA and protein levels in HAEC and that ESX pretreatment significantly decreased SGK1 mRNA and protein levels at both the basal and the TNF-α-stimulated conditions, whereas SPL had no effect on SGK1 mRNA and protein levels. In addition, the TNF-α-induced nuclear factor kappa-light-chain-enhancer of activated B cell activity was suppressed by the treatment with ESX, and it was abrogated by SGK1 overexpression. These results indicated that ESX has direct anti-inflammatory effects in HAEC via the blocking of long-term TNF-α-induced SGK1 activation and that SGK1 could be a key molecule linking cytokine-induced vascular chronic inflammation and MR activation.

• Authors: Hiroyasu Yamamoto, Nao Yoshida, Shinji Kihara
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 80 Issue 4 Pg. 583-591 (10 01 2022) ISSN: 1533-4023 [Electronic] United States
• PMID: 35900901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Glucocorticoids
• NF-kappa B
• Pyrroles
• RNA, Messenger
• Receptors, Mineralocorticoid
• Sulfones
• Tumor Necrosis Factor-alpha
• Spironolactone
• esaxerenone

Topics

• Anti-Inflammatory Agents (pharmacology)
• Cytokines
• Endothelial Cells (metabolism)
• Glucocorticoids (pharmacology)
• Humans
• Inflammation (pathology)
• NF-kappa B (metabolism)
• Pyrroles
• RNA, Messenger
• Receptors, Mineralocorticoid (genetics)
• Spironolactone (pharmacology)
• Sulfones
• Tumor Necrosis Factor-alpha (pharmacology)