A research team led by Prof. WENG Jianping from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS) revealed that insulin-like growth factor-binding protein 6 (IGFBP6) serves as a potential therapeutic target for suppressing endothelial inflammation and atherosclerosis. The study was published in Nature Cardiovascular Research.

Atherosclerotic cardiovascular disease (ASCVD) caused by atherosclerosis is one of the leading causes of death worldwide. Inflammation plays a crucial role in the onset and progression of ASCVD. Previous studies have shown that targeting residual inflammatory risk is critical for ASCVD treatment. Identifying new targets to vascular inflammation may offer new hope for ASCVD treatment.

The team had analyzed the RNA sequencing datasets of patients exposed to atherosclerotic protective therapy and the gene expression datasets from the unstable plaques of atherosclerotic patients using the GEO public database. And it identified IGFBP6, known to play a crucial role in regulating cell cycle, proliferation, and migration, as a potential vascular homeostasis-related molecule. However, the role of IGFBP6 in endothelial homeostasis and atherosclerosis remains unclear.

In this study, the team discovered that IGFBP6 levels were significantly diminished in atherosclerotic plaques and serum from patients with coronary artery disease (CAD). Knockdown of IGFBP6 in endothelial cells increased the expression of inflammatory molecules and monocyte adhesion. Meanwhile, the overexpression of IGFBP6 reversed pro-inflammatory effects induced by disturbed flow (DF) and tumor necrosis factor (TNF). 

Further mechanistic studies revealed that IGFBP6 was transcriptionally regulated by Krüppel-like factor 2 (KLF2) and exerted its anti-inflammatory effects via the major vault protein (MVP)-c-Jun N-terminal kinase (JNK)/nuclear factor kappa B (NF-κB) signaling axis.

In mouse models, systemic and endothelial-specific knockout of IGFBP6 exacerbated diet-induced atherosclerosis, whereas endothelial-specific overexpression of IGFBP6 alleviated atherosclerosis. 

Based on these findings, researchers suggested that the reduction of endothelial IGFBP6 is a trigger for vascular inflammation and atherosclerosis. This study reveals the role of IGFBP6 in regulating endothelial inflammation and atherosclerosis, making it a promising therapeutic target for the treatment of ASCVD and vascular diseases.