Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-kappaB pathway

Area of Science:

• Endocrinology
• Vascular Biology
• Molecular Biology

Background:

• Diabetes mellitus causes endothelial dysfunction, a precursor to vascular complications, primarily driven by hyperglycemia.
• Hyperglycemia-induced oxidative stress and nuclear factor-kappaB (NF-kappaB) activation are key mechanisms contributing to endothelial dysfunction.
• Reduced C-peptide levels are implicated in diabetic vascular dysfunction, but its direct effects on endothelial cells remain largely unexplored.

Purpose of the Study:

• To investigate the in vitro effects of C-peptide on biochemical markers of endothelial dysfunction in human aortic endothelial cells (HAEC).
• To elucidate the role of C-peptide in modulating intracellular signaling pathways, specifically NF-kappaB activation, in the context of hyperglycemia.

Main Methods:

• Human aortic endothelial cells (HAEC) were treated with high glucose (25 mmol/l) in the presence or absence of C-peptide (0.5 nmol/l).
• Vascular cell adhesion molecule-1 (VCAM-1) expression was assessed using RT-PCR and flow cytometry.
• Interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) secretion levels were quantified by ELISA.
• NF-kappaB activation was analyzed via immunoblotting and ELISA.

Main Results:

• C-peptide significantly decreased high glucose-induced VCAM-1 expression and adherence of U-937 cells to HAEC.
• C-peptide reduced the secretion of pro-inflammatory cytokines IL-8 and MCP-1 from HAEC.
• C-peptide suppressed the activation of NF-kappaB in response to high glucose conditions.

Conclusions:

• C-peptide directly counteracts hyperglycemia-induced endothelial dysfunction by modulating VCAM-1 expression and inflammatory mediator secretion.
• The anti-inflammatory and potentially anti-atherogenic effects of C-peptide on endothelial cells are mediated through the suppression of NF-kappaB activation.
• These findings highlight a potential therapeutic role for C-peptide in managing diabetic vascular complications.