14-3-3 protein regulates Ask1 signaling and protects against diabetic cardiomyopathy.
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 14-3-3eta protein mutant (DN 14-3-3eta) after induction of experimental diabetes. The elevation in blood glucose was comparable between wild type (WT) and DN 14-3-3eta mice. However, a marked downregulation of thioredoxin reductase was apparent in DN 14-3-3eta mice compared to WT mice after induction of diabetes. Significant Ask1 activation in DN 14-3-3eta 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 14-3-3eta 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 14-3-3eta 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.
Thandavarayan
Rajarajan A
RA
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Niigata City, Japan.
Watanabe
Kenichi
K
Ma
Meilei
M
Veeraveedu
Punniyakoti T
PT
Gurusamy
Narasimman
N
Palaniyandi
Suresh S
SS
Zhang
Shaosong
S
Muslin
Anthony J
AJ
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D048948:14-3-3 Proteins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D009202:Cardiomyopathies / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography; D006352:Heart Ventricles / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000502:physiology
D048948:14-3-3 Proteins; D001786:Blood Glucose; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse