Researchers identify a natural defense against blood vessel inflammation and atherosclerosis

By Dr. Sanchari Sinha Dutta, Ph.D.Reviewed by Danielle Ellis, B.Sc.Jan 15 2025

This research suggests that IGFBP6 responds to physical forces in blood vessels, helps reduce inflammation, and protects against artery-clogging diseases like atherosclerosis

A study published in Nature Cardiovascular Research identifies an intrinsic anti-inflammatory factor that can be therapeutically targeted to reduce vascular inflammation and atherosclerosis.

Background

Vascular inflammatory diseases, including atherosclerosis, are associated with an imbalance between pro-inflammatory and anti-inflammatory pathways. Cardiovascular diseases caused by atherosclerosis remain a major cause of mortality worldwide despite advancements in treatment.

The majority of current interventions primarily focus on treating the risk factors that cause vascular inflammatory diseases; lipid-lowering medications, blood pressure control medications, and lifestyle changes are among the most widely used preventive interventions. Treatment of acute events primarily involves angioplasty and stents.

Kruppel-like factors 2 and 4 (KLF2/4) are the most widely studied intrinsic factors expressed in vascular endothelial cells. These factors mediate the expression of several anti-inflammatory, anti-oxidative, and anti-thrombotic genes that stabilize the vasculature and reduce vascular inflammation and atherosclerosis risk.

In the study, scientists screened RNA sequencing databases to identify genes that were upregulated in endothelial cells after treatment with lipid-lowering drugs or due to unidirectional laminar fluid shear stress and downregulated in endothelial cells isolated from patients with unstable plaque.   

The main aim of the study was to identify intrinsic factors that counteract vascular inflammation and reduce atherosclerosis risk.

Important observations

The scientists identified insulin-like growth factor binding protein 6 (IGFBP6) as the candidate gene following the initial screening of RNA sequencing databases. Existing evidence indicates that IGFBP5, a paralog of IGFBP6, plays an anti-inflammatory role in endothelial cells, suggesting that IGFBP6 might be involved in vascular resilience.

The researchers conducted global or endothelial cell-specific deletion of IGFBP6 and found an induction in the size of atherosclerotic plaques in hyperlipidemic mice. They also observed larger necrotic cores, thinner fibrous caps, and greater immune cell content. These findings indicate the development of vulnerable atherosclerotic plaques that are at higher risk of rupture.

Conversely, they observed a reduction in plaque size and an induction in the markers of plaque stability after overexpressing IGFBP6 in endothelial cells.

The in vitro experiments they conducted using cultured endothelial cells indicated that downregulation of IGFBP6 is associated with increased expression of several inflammatory genes and pathways and reduced leukocyte adhesion, which is a hallmark of vascular inflammation.

Upon overexpressing IGFBP6 in these cells, they observed suppression of inflammatory events. They further observed that the upregulation of IGFBP6 expression by atheroprotective laminar shear stress is dependent on KLF2 expression and that KLF2 is physically associated with the IGFBP6 promoter.

These findings indicate that IGFBP6 is a novel KLF2-dependent gene that plays an anti-inflammatory role in vascular endothelial cells.

Anti-inflammatory mode of action of IGFBP6

The scientists conducted immunoprecipitation and mass spectrometry-based proteomics and observed that major vault protein (MVP) directly interacts with IGFBP6 with high affinity.

Vaults are large barrel-shaped protein-–RNA complexes associated with several biological processes, including antiviral immunity, signal transduction, chemotherapeutic drug resistance, apoptosis resistance, and nuclear-cytoplasmic transport.

Existing evidence indicates that MVP can reduce atherosclerosis in mice by regulating c-JUN degradation, inhibiting STAT signaling, and inhibiting both c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB) pathways in macrophages.

The scientists here observed that downregulation of MPV reverses the anti-inflammatory effects of IGFBP6 on endothelial cells, including reduced JNK and NF-κB activity and immune cell adhesion.

Regarding the mode of action of IGFBP6, they reported that the binding of IGFBP to MPV increases its interaction with and inhibition of apoptosis signal-regulating kinase 1 (ASK1), which is an adaptor protein required for JNK and NF-κB activation. ASK1 appeared to be a direct target of IGFBP6, and its inhibition by IGFBP6 led to the suppression of inflammatory pathways in vascular endothelial cells.

Study significance

The study identifies IGFBP6 as a homeostasis-associated molecule that reduces endothelial inflammation and atherosclerosis. Mechanistically, IGFBP6 appears to mediate its anti-inflammatory actions directly via the MVP–JNK –NF-κB signaling axis.

The scientists propose that the reduction of endothelial IGFBP6 is a predisposing factor in vascular inflammation and atherosclerosis, which can be therapeutically targeted.

Augmenting KLF2/4 levels in endothelial cells is currently considered a promising approach for treating cardiovascular diseases. Further studies are needed to more conclusively understand the importance of IGFBP6, which is known to be a KLF2/4 target gene.