RRC ID 74244
Author Yamamoto H, Yoshida N, Kihara S.
Title Esaxerenone Blocks Vascular Endothelial Inflammation Through SGK1.
Journal J Cardiovasc Pharmacol
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.
Volume 80(4)
Pages 583-591
Published 2022-10-1
DOI 10.1097/FJC.0000000000001316
PII 00005344-202210000-00013
PMID 35900901
MeSH 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
IF 2.598
Human and Animal Cells Hep G2(RCB1886)