Glycogen synthase kinase 3beta together with 14-3-3 protein regulates diabetic cardiomyopathy: effect of losartan and tempol.
Glycogen synthase kinase (GSK) 3beta is a multifunctional protein that positively regulates myocardial apoptosis and negatively regulates hypertrophy. However, the role of GSK3beta in the diabetic myocardium is largely unknown. We found that GSK3beta became more active (less phosphorylated at serine 9) via decreased Akt phosphorylation, in parallel to c-Jun NH2 terminal kinase activation, which correlated with increased activated caspase 3 and myocardial apoptosis 3 days after streptozotocin (STZ) injection in mice. However, 28 days after STZ injection, GSK3beta became inactive, which correlated with the enhanced protein kinase C beta2 and p38 mitogen activated protein kinase expression, nuclear translocation of nuclear factor of activated T cells c3, cardiac hypertrophy and fibrosis. All of the above parameters were exacerbated in dominant-negative 14-3-3 transgenic mice. Our results suggest that GSK3beta together with 14-3-3 protein plays essential roles in the signaling of diabetic cardiomyopathy, and treatment with either losartan or tempol prevents these changes.
Gurusamy
Narasimman
N
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 5-13-2 Kamishinei-Cho, Niigata City, Japan.
Watanabe
Kenichi
K
Ma
Meilei
M
Prakash
Paras
P
Hirabayashi
Kenichi
K
Zhang
Shaosong
S
Muslin
Anthony J
AJ
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D048948:14-3-3 Proteins / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy; D009202:Cardiomyopathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D004719:Endomyocardial Fibrosis / Q000188:drug therapy; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D013113:Spin Labels; D013311:Streptozocin / Q000494:pharmacology
D048948:14-3-3 Proteins; D001786:Blood Glucose; D003497:Cyclic N-Oxides; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D013113:Spin Labels; D000804:Angiotensin II; D013311:Streptozocin; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019808:Losartan; C001803:tempol