Coordinated augmentation of NFAT and NOD signaling mediates proliferative VSMC phenotype switch under hyperinsulinemia

•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.

AimAlthough 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 resultsHuman 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).DiscussionThis 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.