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Publications

Journal Article Epublish

PubMed: 42898388 DOI: 10.1016/j.gendis.2026.102212

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

Genes Dis 14(2):102212

Authors: Jinxuan Wang, Xiaoqi Zhou, Yuanyuan Liu, Jianxiong Xu, Yanzhu Long, Shuai Hu, Cheng Wang, Liqiong Yan, Chen Yang, Langtao Wang, Liping Luo, Tao Yu, Yang Shen, Yu Li, Xiangyu Zhou, Guixue Wang, Xiaozhen Dai

Affiliations

  • Aging Mechanisms and Interventions Key Laboratory of Sichuan Province, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan 610500, China.
  • School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan 610500, China.
  • College of Health Management, Xihua University, Chengdu, Sichuan 610039, China.
  • Key Laboratory of Target Discovery and Protein Drug Development in Major Diseases of Sichuan Higher Education Institutes, School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, Sichuan 610500, China.
  • School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan 610500, China.
  • Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China.
  • CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • Department of Cardiology, The Affiliated Hospital of Southwest Medical University and Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research and Institute of Metabolic Diseases, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • Key Laboratory for Biorheological Science and Technology of the Ministry of Education, National Local Joint Engineering Lab for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing 400044, China.
  • Hubei Shizhen Laboratory, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, China.
  • Aging Mechanisms and Interventions Key Laboratory of Sichuan Province, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan 610500, China. Key Laboratory of Target Discovery and Protein Drug Development in Major Diseases of Sichuan Higher Education Institutes, School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, Sichuan 610500, China.

Abstract

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.

MeSH

Cells, Hepatocytes, Transcription Factors, Liver, Exosomes, Endothelial Cells, Atherosclerosis