A role for calcium in resistin transcriptional activation in diabetic hearts

Sci Rep. 2018 Oct 23;8(1):15633. doi: 10.1038/s41598-018-34112-4.

Abstract

The adipokine resistin has been proposed to link obesity, insulin resistance and diabetes. We have previously reported that diabetic hearts express high levels of resistin while overexpression of resistin in adult rat hearts gives rise to a phenotype resembling diabetic cardiomyopathy. The transcriptional regulation of resistin in diabetic cardiac tissue is currently unknown. This study investigated the mechanism of resistin upregulation and the role of Serca2a in its transcriptional suppression. We demonstrate that restoration of Ca2+ homeostasis in diabetic hearts, through normalization of Serca2a function genetically and pharmacologically, suppressed resistin expression via inhibition of NFATc. H9c2 myocytes stimulated with high-glucose concentration or Ca2+ time-dependently increased NFATc and resistin expression while addition of the Ca2+ chelator BAPTA-AM attenuated this effect. NFATc expression was enhanced in hearts from ob/ob diabetic and from cardiac-specific Serca2a-/- mice. Similarly, NFATc increased resistin expression in myocytes cultured in low glucose while the NFATc inhibitor VIVIT blocked glucose-induced resistin expression, suggesting that hyperglycemia/diabetes induces resistin expression possibly through NFATc activation. Interestingly, overexpression of Serca2a or VIVIT mitigated glucose-stimulated resistin and NFATc expression and enhanced AMPK activity, a downstream target of resistin signaling. NFATc direct activation of resistin was verified by resistin promoter luciferase activity and chromatin-immunoprecipitation analysis. Interestingly, activation of Serca2a by a novel agonist, CDN1163, mirrored the effects of AAV9-Serca2a gene transfer on resistin expression and its promoter activity and AMPK signaling in diabetic mice. These findings parse a role for Ca2+ in resistin transactivation and provide support that manipulation of Serca2a-NFATc-Resistin axis might be useful in hyper-resistinemic conditions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenylate Kinase / metabolism
  • Allosteric Regulation / drug effects
  • Animals
  • Calcium / metabolism*
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetic Cardiomyopathies / genetics*
  • Diabetic Cardiomyopathies / pathology
  • Down-Regulation / genetics
  • Enzyme Activation / drug effects
  • Glucose / metabolism
  • Male
  • Mice, Inbred C57BL
  • Myocardium / metabolism*
  • Myocardium / pathology*
  • NFATC Transcription Factors / metabolism
  • Organ Specificity / drug effects
  • Promoter Regions, Genetic / genetics
  • Rats
  • Resistin / genetics*
  • Resistin / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Small Molecule Libraries / pharmacology
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • NFATC Transcription Factors
  • Resistin
  • Small Molecule Libraries
  • Adenylate Kinase
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Glucose
  • Calcium