14-3-3 protein regulates Ask1 signaling and protects against diabetic cardiomyopathy

Rajarajan A. Thandavarayan, Kenichi Watanabe, Meilei Ma, Punniyakoti T. Veeraveedu, Narasimman Gurusamy, Suresh S. Palaniyandi, Shaosong Zhang, Anthony J. Muslin, Makoto Kodama, Yoshifusa Aizawa

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


Mammalian 14-3-3 proteins are dimeric phosphoserine-binding proteins that participate in signal transduction and regulate several aspects of cellular biochemistry. Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. In order to study the pathogenic changes underlying diabetic cardiomyopathy, we examined the role of 14-3-3 protein and apoptosis signal-regulating kinase 1 (Ask1) signaling by using transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3η protein mutant (DN 14-3-3η) after induction of experimental diabetes. The elevation in blood glucose was comparable between wild type (WT) and DN 14-3-3η mice. However, a marked downregulation of thioredoxin reductase was apparent in DN 14-3-3η mice compared to WT mice after induction of diabetes. Significant Ask1 activation in DN 14-3-3η after diabetes induction was evidenced by pronounced de-phosphorylation at Ser-967 and intense immunofluorescence observed in left ventricular (LV) sections. Echocardiographic analysis revealed that cardiac functions were notably impaired in diabetic DN 14-3-3η mice compared to diabetic WT mice. Marked increases in myocardial apoptosis, cardiac hypertrophy, and fibrosis were observed with a corresponding up-regulation of atrial natriuretic peptide and galectin-3, as well as a downregulation of sarcoendoplasmic reticulum Ca2+ ATPase2 expression. Furthermore, diabetic DN 14-3-3η mice displayed significant reductions of platelet-endothelial cell adhesion molecule-1 staining as well as endothelial nitric acid synthase and vascular endothelial growth factor expression. In conclusion, our data suggests that enhancement of 14-3-3 protein could provide a novel therapeutic strategy against hyperglycemia-induced left ventricular dysfunction and can limit the progression of diabetic cardiomyopathy by regulating Ask1 signaling.

Original languageEnglish (US)
Pages (from-to)1797-1806
Number of pages10
JournalBiochemical pharmacology
Issue number9
StatePublished - May 1 2008


  • 14-3-3 protein
  • Apoptosis signal-regulating kinase 1
  • Diabetic cardiomyopathy
  • Endothelial cells
  • Fibrosis
  • Hypertrophy
  • Thioredoxin reductase

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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