Targeting hepatic CREBZF protects against atherosclerosis via exosomal miR-210-3p mediated inhibition of endothelial inflammation.

Cardiovascular diseases (CVDs) continue to be the primary cause of mortality globally. Abnormal liver function has been widely recognized as an independent risk factor for atherosclerotic CVDs. However, how alterations in liver function affect distal vascular function remains largely unknown. CREBZF, a bZIP transcription factor of the CREB/ATF family, has been identified as a driver of hepatic steatosis and fibrosis. Here, we provide the first demonstration that hepatic CREBZF acts as a critical regulator driving atherosclerotic progression. In vivo, hepatic-specific deletion of CREBZF attenuates endothelial inflammation and reduces macrophage infiltration, thereby ameliorating plaque formation in both high-fat diet-fed and spontaneous atherosclerotic mouse models. In vitro, overexpression or knockdown of CREBZF in hepatocytes correspondingly promotes or attenuates endothelial inflammation. Mechanistically, hepatocyte CREBZF regulates endothelial inflammation via exosomes, an effect independent of cholesterol metabolism or of soluble cytokines. Furthermore, CREBZF dynamically modulates the expression of exosomal miR-210-3p and its subsequent levels in recipient endothelial cells. miR-210-3p, in turn, suppresses endothelial inflammation by targeting C-Rel, a component of the NF-κB transcription factor family. Importantly, the pro-inflammatory effect of exosomes derived from CREBZF-overexpressing hepatocytes on endothelial cells is abrogated by a miR-210-3p mimic. Collectively, these findings unveil a novel mechanism by which hepatic CREBZF regulates atherosclerosis through liver-vascular crosstalk mediated by the exosomal miR-210-3p/C-Rel signaling axis, suggesting a potential therapeutic strategy for atherosclerotic CVDs.