Extracellular histones induce inflammation and senescence of vascular smooth muscle cells by activating the AMPK/FOXO4 signaling pathway

Abstract

Sepsis is an abnormal immune-in ammatory response that is mainly caused by infection. It can lead to life-threatening organ dysfunction and death. Severely damaged tissue cells will release intracellular histones into the circulation as damage-related molecular patterns (DAMPs) to accelerate the systemic immune response. Although various histone-related cytotoxicity mechanisms have been explored, those that affect extracellular histones involved in vascular smooth muscle cell (VSMC) dysfunction are yet to be determined. We found that extracellular histones induced senescence and in ammatory response in a dose-dependent manner in cultured VSMCs. Histone treatment signi cantly promoted apoptosisassociated speck-like protein containing CARD (ASC) as well as NACHT, LRR and PYD domainscontaining protein 3 (NLRP3) interaction of in ammasomes in VSMCs. Forkhead box protein O4 (FOXO4), which is a downstream effector molecule of extracellular histones, was found to be involved in histone-regulated VSMC in ammatory response and senescence. Furthermore, the 5'-AMP-activated protein kinase (AMPK) signaling pathway was con rmed to mediate extracellular histone-induced FOXO4 expression, and blocking this signaling pathway with an inhibitor can suppress vascular in ammation induced by extracellular histones in vivo and in vitro. These results suggest that the AMPK/FOXO4 pathway is a potential target in treating histone-mediated organ injury.

FGF21 overexpression alleviates VSMC senescence in diabetic mice by modulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway

“…Recent studies have shown that activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a key role in ROS-mediated VSMC senescence [ 12 , 13 ]. However, further research is still needed to understand the relationship between the NLRP3 inflammasome and ROS production.…”