Dominant negative 14-3-3 promotes cardiomyocyte apoptosis in early stage of type I diabetes mellitus through activation of JNK.
14-3-3 family members are dimeric, phosphoserine binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. Recently, cardiomyocyte apoptosis has been characterized in type I diabetes mellitus. In order to study the molecular mechanism underlying diabetes-induced cardiomyocyte apoptosis, we examined the role of 14-3-3 protein and MAPK pathways in transgenic mice with cardiac specific expression of dominant negative 14-3-3eta (DN-14-3-3). p38 MAPK was highly activated 1, 28, and 56 days after diabetes induction by streptozotocin, whereas peak JNK activation was found on day 3 and decreased afterwards. In contrast, ERK1/2 were not activated in diabetic myocardium. Cardiomyocyte apoptosis was peaked on day 3 and decreased on 7, 28, and 56 days. p38 MAPK and JNK activation as well as cardiomyocyte apoptosis were greatly increased in DN-14-3-3 mice relative to non-transgenic mice. Moreover, we found a significant correlation between JNK activation and apoptosis in diabetic myocardium. These results indicate for the first time that 14-3-3 protein plays a critical anti-apoptotic role in diabetic myocardium by inhibiting the JNK pathway.
Gurusamy
Narasimman
N
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, Japan.
Watanabe
Kenichi
K
Ma
Meilei
M
Zhang
Shaosong
S
Muslin
Anthony J
AJ
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D048948:14-3-3 Proteins; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D005799:Genes, Dominant / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009929:Organ Size; D015398:Signal Transduction; D013311:Streptozocin; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D048948:14-3-3 Proteins; D001786:Blood Glucose; D013311:Streptozocin; D014446:Tyrosine 3-Monooxygenase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases