Highlights
- •Atherosclerosis is characterized by endothelial dysfunction, smooth muscle cell proliferation and inflammation.
- •Our study shows the role of transcription factor, NFATc1 in hyperinsulinemia induced proliferation and migration of VSMCs.
- •This study advocates the coordinated augmentation of NFATc1 and NOD signaling in the proliferation and migration of VSMCs.
- •In patients with type 2 diabetes, expression of NFATc1 and NOD1/2 showed positive correlation with insulin resistance.
Abstract
Aim
Although hyperglycemia has been demonstrated to play a significant role in the vascular
disease associated with type 2 diabetes, the mechanisms underlying hyperinsulinemia
mediated vascular dysfunction are not well understood. We have analyzed whether hyperinsulinemia
could activate NFAT (Nuclear factor of activated T cells) signaling and thereby influence
vascular smooth muscle cell (VSMC) migration and proliferation, a major event in the
progression of atherosclerosis.
Methods and results
Human aortic VSMCs upon chronic insulin treatment exhibited increased expression of
NFATc1 both at the mRNA and protein levels. The mechanistic role of NFAT in VSMC migration
and proliferation was examined using 11R-VIVIT, a cell permeable NFAT specific inhibitor,
where it reduced the insulin effect on VSMC, which was further substantiated by over
expression or silencing of NFATc1gene (p < 0.05). This study also report for the first
time the role of NFAT in NOD (Nucleotide oligomerization domain) mediated innate immune
signaling and its significance in insulin effect on VSMCs. mRNA expression of NOD
was up regulated when cells were treated with insulin or ligands whereas pretreatment
with 11R-VIVIT reversed this effect (p < 0.05). Our study uphold the clinical significance
as we observed an increased mRNA expression of NFATc1 in monocytes isolated from patients
with type 2 diabetes which correlated positively with insulin resistance and glycemic
load (p < 0.05).
Discussion
This study suggests that targeted NFAT inhibition can be an effective strategy to
coordinately quench insulin induced proliferative and inflammatory responses along
with innate immunity alterations in vascular smooth muscle cells, which underlie atherosclerosis.
Keywords
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Article info
Publication history
Published online: January 12, 2016
Accepted:
January 5,
2016
Received in revised form:
November 20,
2015
Received:
September 14,
2015
Identification
Copyright
© 2016 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
