SGK1 inhibition exerts atheroprotective effects in vascular endothelial cells.

Mineralocorticoid receptor antagonists (MRA) exert anti-atherosclerotic properties in vivo through their combined effects on various cells and tissues. We previously found a significant interaction between TNFα-induced inflammatory pathways and mineralocorticoid receptor signaling, particularly involving serum/glucocorticoid-regulated kinase 1 (SGK1), in vascular endothelial cells. This study further elucidated the specific roles of SGK1 in vascular endothelial function. In SGK1-knockdown human aortic endothelial cells (HAECs), TNFα-induced inflammation-related molecules (e.g., E-selectin, VCAM-1, PAI-1, and MCP-1) were significantly downregulated compared to controls. Monocyte adhesion was also significantly reduced in SGK1-knockdown human umbilical vein endothelial cells, regardless of TNFα stimulation. Additionally, in these SGK1-knockdown HAECs, there was a significant attenuation of the TNFα-induced reduction of both total and phosphorylated protein levels of endothelial nitric oxide synthase (eNOS), accompanied by increased phosphorylation of protein kinase B (AKT) and adenosine monophosphate-activated protein kinase (AMPK). The upregulation of eNOS caused by SGK1 knockdown occurred at the transcriptional level alongside an increase in Krüppel-like factor 2 (KLF2) mRNA. Importantly, KLF2 knockdown negated this effect. The increase in eNOS protein levels observed with SGK1 knockdown was not seen in HAECs with combined SGK1 and KLF2 knockdown. These findings suggest a notable role of SGK1 in promoting inflammation and inhibiting vasodilation through multiple mechanisms, propositioning SGK1 as a potential therapeutic target for protecting vascular endothelial function.