Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Clusterin (CLU) is a stress-responding protein with cytoprotective roles.
• The specific function of clusterin in diabetes-induced endothelial dysfunction remains unclear.
• Endothelial dysfunction is a key factor in vascular complications of diabetes.

Purpose of the Study:

• To investigate the role of clusterin in diabetes-induced endothelial dysfunction.
• To elucidate the molecular mechanisms underlying clusterin's effects in diabetic conditions.
• To explore clusterin's impact on mitochondrial dynamics and inflammation.

Main Methods:

• Utilized two diabetes models: db/db mice and streptozotocin (STZ)-induced diabetic mice.
• Employed adenoviral clusterin overexpression and clusterin silencing in vitro.
• Assessed endothelial function, inflammatory markers (ICAM-1, VCAM-1), monocyte adhesion, mitochondrial fission/ROS production, and AMPK/ACC phosphorylation.

Main Results:

• Clusterin overexpression improved endothelium-dependent vasodilation and reduced ICAM-1/VCAM-1 expression in diabetic mice.
• In vitro, clusterin reduced pro-inflammatory cytokines, suppressed monocyte adhesion, mitigated mitochondrial fission, and decreased mitochondrial ROS production.
• Clusterin activated AMP-activated protein kinase (AMPK) signaling, which was crucial for its protective effects on mitochondrial dynamics.

Conclusions:

• Clusterin exerts protective effects against diabetes-induced endothelial dysfunction.
• Clusterin mitigates endothelial inflammation and dysfunction by inhibiting mitochondrial fragmentation.
• AMPK activation is a key mechanism by which clusterin modulates mitochondrial dynamics and exerts its beneficial effects in diabetic conditions.