title: SOCS-1 inhibits TNF-alpha-induced cardiomyocyte apoptosis via ERK1/2 pathway activation.
abstract: Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine involved in mitogen-activated protein kinase (MAPK) signaling pathways, contributes to the pathogenesis of cardiovascular diseases. Recently, suppressor of cytokine signaling-1 (SOCS-1) has been shown to modulate responses to TNF-alpha. However, whether SOCS-1 suppresses TNF-alpha-dependent apoptotic processes in cardiomyocytes and whether MAPK pathways mediate this effect have not been clearly elucidated. This study was carried out to define the role of SOCS-1 on TNF-alpha-induced apoptosis in neonatal rat cardiomyocytes and to investigate the signal pathways involved. Exposure to TNF-alpha (10 ng/ml for 24 h) significantly increased the number of apoptotic cells, the activity of caspase-8 and caspase-3, and the Bax/Bcl-xl ratio. In contrast, adenovirus-mediated gene transfer of SOCS-1 reversed the pro-apoptotic effect of TNF-alpha. Additionally, preincubation of cardiomyocytes with the extracellular signal-regulated kinase-1 and -2 (ERK1/2) inhibitor PD98059 attenuated the protective effect of SOCS-1, but the p38-MAPK inhibitor SB203580 and the c-Jun amino-terminal kinase (JNK) inhibitor SP600125 had no effect. Furthermore, the TNF-alpha-induced decrease in the phosphorylation of ERK1/2 was abolished by overexpression of SOCS-1. These findings suggest that SOCS-1 prevents TNF-alpha-induced apoptosis in cardiac myocytes via ERK1/2 pathway activation.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University School of Medicine, 238 JieFang Road, Wuchang, Wuhan 430060, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Qizhu
authors.initials: Q
authors.lastname: Tang
authors.forename: Difei
authors.initials: D
authors.lastname: Shen
authors.forename: Sheng
authors.initials: S
authors.lastname: Peng
authors.forename: Qian
authors.initials: Q
authors.lastname: Zheng
authors.forename: Haipeng
authors.initials: H
authors.lastname: Guo
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; D053148:Caspase 3; D053181:Caspase 8