Different contributions of STAT3, ERK1/2, and PI3-K signaling to cardiomyocyte hypertrophy by cardiotrophin-1  

作　　者：Ze-junTIAN WeiCUI Yong-junLI Yu-mingHAO JunDU FanLIU HuiZHANG Xiu-guangZU Su-yunLIU LiCHEN WeiAN 

机构地区：[1]DepartmentofCardiology,SecondHospitalofHebeiMedicalUniversity,Shijiazhuang050000,China [2]DepartmentofCellBiologyandMunicipalLaboratoryforLiverProtection,Beijing100054,China

出　　处：《Acta Pharmacologica Sinica》2004年第9期1157-1164,共8页中国药理学报（英文版）

基　　金：ProjectsupportedbytheHebeiProvincialScientific&Tech-nologicalResearchGrants(No01276183D,00276149D,and02-025)andSpecialGrantofMunicipalKeyLaboratoryBeijing.

摘　　要：AIM: To assess the contribution of signal transducer and activator of transcription 3 (JAK-STAT3) pathway, extracellular signal-regulated kinases1/2 (ERK1/2) pathway, and phosphatidylinositol 3-kinase (PI3-K) pathway to cardiomyocytes hypertrophy induced by cardiotrophin-1 (CT-1), a new member of interleukin-6 (IL-6) family of cytokines. METHODS: STAT3, ERKl/2, and PI3-K were assessed by Western blot analysis. Activity of ERKl/2 was also confirmed by in-gel kinase assay. Hypertrophy of cardiomyocyte was evaluated by [3H]leucine incorporation and cellular protein-to-DNA ratio. RESULTS: CT-1 simultaneously activated phosphorylation of STAT3, ERKl/2, and PI3-K in rat cardiomyocytes. Parthenolide, an inhibitor of STAT, suppressed CT-1-induced [3H]leucine incorporation by 88.3 % and protein-to-DNA ratio by 75.0 %. U0126, an MEK1/2 inhibitor, increased CT-1-induced the phosphorylation of STAT3 in a dose-dependent manner and, consistently, augmented CT-1-induced increase in [3H]leucine incorporation and cellular protein-to-DNA ratio by 17.6 % and 16.3 %, respectively. Wortmannin, a PI3-K inhibitor, did not influence CT-1-induced [3H]leucine incorporation and cellular protein-to-DNA ratio. CONCLUSION: The hypertrophic effect of CT-1 was essentially mediated by STAT3, independent of PI3-K, and negatively regulated by ERKl/2 via inhibiting the phosphorylation of STAT3. The interaction between STAT3 and ERKl/2 in CT-1-induced signaling contributes to development of cardiac hypertrophy.AIM: To assess the contribution of signal transducer and activator of transcription 3 (JAK-STAT3) pathway, extracellular signal-regulated kinases1/2 (ERK1/2) pathway, and phosphatidylinositol 3-kinase (PI3-K) pathway to cardiomyocytes hypertrophy induced by cardiotrophin-1 (CT-1), a new member of interleukin-6 (IL-6) family of cytokines. METHODS: STAT3, ERKl/2, and PI3-K were assessed by Western blot analysis. Activity of ERKl/2 was also confirmed by in-gel kinase assay. Hypertrophy of cardiomyocyte was evaluated by [3H]leucine incorporation and cellular protein-to-DNA ratio. RESULTS: CT-1 simultaneously activated phosphorylation of STAT3, ERKl/2, and PI3-K in rat cardiomyocytes. Parthenolide, an inhibitor of STAT, suppressed CT-1-induced [3H]leucine incorporation by 88.3 % and protein-to-DNA ratio by 75.0 %. U0126, an MEK1/2 inhibitor, increased CT-1-induced the phosphorylation of STAT3 in a dose-dependent manner and, consistently, augmented CT-1-induced increase in [3H]leucine incorporation and cellular protein-to-DNA ratio by 17.6 % and 16.3 %, respectively. Wortmannin, a PI3-K inhibitor, did not influence CT-1-induced [3H]leucine incorporation and cellular protein-to-DNA ratio. CONCLUSION: The hypertrophic effect of CT-1 was essentially mediated by STAT3, independent of PI3-K, and negatively regulated by ERKl/2 via inhibiting the phosphorylation of STAT3. The interaction between STAT3 and ERKl/2 in CT-1-induced signaling contributes to development of cardiac hypertrophy.

关 键 词：cardiac hypertrophy signal transduction CARDIOTROPHIN-1 MAP kinase signaling system trans- activators 1-phosphatidylinosito1 3-kinase 

分 类 号：R541[医药卫生—心血管疾病]