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- Diabetologia. 2008 May 21. [Epub ahead of print]
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Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-kappaB pathway.
Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children’s Hospital of Pittsburgh, 3460 Fifth Avenue, Pittsburgh, PA, 15213, USA, luppip@pitt.edu.
AIMS/HYPOTHESIS: Endothelial dysfunction in diabetes is predominantly caused by hyperglycaemia leading to vascular complications through overproduction of oxidative stress and activation of the transcription factor nuclear factor-kappaB (NF-kappaB).
Many studies have suggested that decreased circulating levels of C-peptide may play a role in diabetic vascular dysfunction.
To date, the possible effects of C-peptide on endothelial cells and intracellular signalling pathways are largely unknown.
We therefore investigated the effect of C-peptide on several biochemical markers of endothelial dysfunction in vitro.
To gain insights into potential intracellular signalling pathways affected by C-peptide, we tested NF-kappaB activation, since it is known that inflammation, secondary to oxidative stress, is a key component of vascular complications and NF-kappaB is a redox-dependent transcription factor.
METHODS: Human aortic endothelial cells (HAEC) were exposed to 25 mmol/l glucose in the presence of C-peptide (0.5 nmol/l) for 24 h and tested for expression of the gene encoding vascular cell adhesion molecule-1 (VCAM-1) by RT-PCR and flow cytometry.
Secretion of IL-8 and monocyte chemoattractant protein-1 (MCP-1) was measured by ELISA. NF-kappaB activation was analysed by immunoblotting and ELISA.
RESULTS: Physiological concentrations of C-peptide affect protection in relation to ... high glucose-induced endothelial dysfunction by...
(1) decreasing VCAM-1 expression and U-937 cell adherence to HAEC;
(2) reducing secretion of IL-8 and MCP-1; and
(3) suppressing NF-kappaB activation.
CONCLUSIONS/INTERPRETATION: During hyperglycaemia, C-peptide directly affects VCAM-1 expression and both MCP-1 and IL-8 HAEC secretion by reducing NF-kappaB activation.
These effects suggest a physiological anti-inflammatory (and potentially anti-atherogenic) activity of C-peptide on endothelial cells.
PMID: 18493738
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