TY - JOUR
T1 - 14-3-3 protein regulates Ask1 signaling and protects against diabetic cardiomyopathy
AU - Thandavarayan, Rajarajan A.
AU - Watanabe, Kenichi
AU - Ma, Meilei
AU - Veeraveedu, Punniyakoti T.
AU - Gurusamy, Narasimman
AU - Palaniyandi, Suresh S.
AU - Zhang, Shaosong
AU - Muslin, Anthony J.
AU - Kodama, Makoto
AU - Aizawa, Yoshifusa
N1 - Funding Information:
We thank Sayako Mito, Hiroka Tanaka, Flori R.S., and Wawaimuli A. for their assistance in this work. This research was supported by grants from Yujin Memorial Grant; the Ministry of Education, Culture, Sports, Science and Technology of Japan; and Promotion and Mutual Aid Corporation for Private Schools of Japan.
PY - 2008/5/1
Y1 - 2008/5/1
N2 - 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.
AB - 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.
KW - 14-3-3 protein
KW - Apoptosis signal-regulating kinase 1
KW - Diabetic cardiomyopathy
KW - Endothelial cells
KW - Fibrosis
KW - Hypertrophy
KW - Thioredoxin reductase
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U2 - 10.1016/j.bcp.2008.02.003
DO - 10.1016/j.bcp.2008.02.003
M3 - Article
C2 - 18342293
AN - SCOPUS:41949122949
SN - 0006-2952
VL - 75
SP - 1797
EP - 1806
JO - Biochemical pharmacology
JF - Biochemical pharmacology
IS - 9
ER -