Endothelial IGFBP6 suppresses vascular inflammation and atherosclerosis.
Summary
IGFBP6 is downregulated in human atherosclerosis and acts within endothelial cells to blunt inflammation by inhibiting MVP–JNK/NF-κB signaling. Loss of IGFBP6 exacerbates, while endothelial overexpression protects against, diet- and disturbed-flow–induced atherosclerosis, nominating IGFBP6 as a therapeutic target.
Key Findings
- IGFBP6 levels are decreased in human atherosclerotic arteries and serum.
- Endothelial IGFBP6 knockdown increases inflammatory gene expression and monocyte adhesion; overexpression reverses disturbed flow/TNF-induced inflammation.
- IGFBP6 signals via the MVP–JNK/NF-κB axis; IGFBP6 deficiency aggravates, while endothelial overexpression protects against, atherosclerosis in mice.
Clinical Implications
IGFBP6 may serve as a biomarker for vascular risk and a candidate for endothelium-targeted therapies to reduce inflammation and atherosclerosis.
Why It Matters
Identifies an endothelial-intrinsic, targetable brake on vascular inflammation with convergent human, mechanistic, and in vivo evidence.
Limitations
- Translational relevance to human therapeutic modulation of IGFBP6 requires clinical studies.
- Potential off-target or systemic effects of modulating IGFBP6 were not fully characterized.
Future Directions
Develop endothelium-targeted strategies to augment IGFBP6, validate MVP–JNK/NF-κB modulation in human endothelium ex vivo, and test biomarker utility in prospective cohorts.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- IV - Mechanistic in vitro studies with supportive in vivo mouse genetics and human observational data
- Study Design
- OTHER