title: Coordinated augmentation of NFAT and NOD signaling mediates proliferative VSMC phenotype switch under hyperinsulinemia.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cell and Molecular Biology, Madras Diabetes Research Foundation, Dr. Mohan's Diabetes Specialities Centre Gopalapuram, Chennai, India. Electronic address: shinyabhijit@gmail.com.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Shiny
authors.affiliation: Department of Cell and Molecular Biology, Madras Diabetes Research Foundation, Dr. Mohan's Diabetes Specialities Centre Gopalapuram, Chennai, India.
authors.forename: Bhaskaran
authors.initials: B
authors.lastname: Regin
authors.affiliation: Department of Cell and Molecular Biology, Madras Diabetes Research Foundation, Dr. Mohan's Diabetes Specialities Centre Gopalapuram, Chennai, India.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Mohan
authors.affiliation: Department of Cell and Molecular Biology, Madras Diabetes Research Foundation, Dr. Mohan's Diabetes Specialities Centre Gopalapuram, Chennai, India.
authors.forename: Muthuswamy
authors.initials: M
authors.lastname: Balasubramanyam
mesh_terms: D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007113:Immunity, Innate; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053472:Nod Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
chemical_list: D001786:Blood Glucose; D007328:Insulin; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053472:Nod Signaling Adaptor Proteins; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D009842:Oligopeptides; C121611:VIVIT peptide
keywords: Atherosclerosis; Diabetes; Innate immunity; NFAT; Vascular smooth muscle cells