CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Endothelial dysfunction in hyperglycemia involves inflammation and altered cell behavior.
• The adapter molecule CIKS (connection to IKK and SAPK/JNK) regulates inflammatory pathways like NF-κB and AP-1.
• CIKS plays a role in inflammation and injury processes.

Purpose of the Study:

• To investigate the role of CIKS in high glucose-induced endothelial dysfunction.
• To elucidate the molecular mechanisms by which CIKS mediates hyperglycemia's effects on endothelial cells.
• To assess the therapeutic potential of targeting CIKS in diabetic vascular complications.

Main Methods:

• Utilized high glucose (HG) exposure in endothelial cells (ECs) with and without CIKS knockdown.
• Investigated reactive oxygen species (ROS) generation via Nox4.
• Employed coimmunoprecipitation and immunoblotting to study protein interactions.
• Analyzed NF-κB and AP-1 signaling pathways, including nuclear translocation.
• Examined expression of inflammatory mediators and adhesion molecules.
• Used mouse models of diabetes (streptozotocin-induced, NOD, Akita) to validate findings in vivo.

Main Results:

• CIKS knockdown reversed HG-induced endothelial-monocyte adhesion and impaired EC migration.
• HG increased CIKS expression in ECs through Nox4-dependent ROS generation.
• HG enhanced CIKS transcription and promoter activity via Nox4, ROS, AP-1, and C/EBP.
• HG treatment increased physical association between CIKS, IKKβ, and JNK.
• CIKS knockdown inhibited HG-induced phosphorylation of IKKβ/JNK, nuclear translocation of p65/c-Jun, and downstream inflammatory gene expression.
• Deleterious metabolic products of hyperglycemia and aortas from diabetic mice showed increased ROS and CIKS expression.

Conclusions:

• CIKS is a critical mediator of high glucose-induced endothelial dysfunction.
• CIKS regulates NF-κB and AP-1 signaling pathways in response to hyperglycemia.
• Targeting CIKS presents a potential therapeutic strategy for vascular diseases associated with diabetes and atherosclerosis.