title: c-Src/Pyk2/EGFR/PI3K/Akt/CREB-activated pathway contributes to human cardiomyocyte hypertrophy: Role of COX-2 induction.
abstract: Thrombin and COX-2 regulating cardiac hypertrophy are via various signaling cascades. Several transcriptional factors including CREB involve in COX-2 expression. However, the interplay among thrombin, CREB, and COX-2 in primary human neonatal ventricular cardiomyocytes remains unclear. In this study, thrombin-induced COX-2 promoter activity, mRNA and protein expression, and PGE2 synthesis were attenuated by pretreatment with the inhibitors of c-Src (PP1), Pyk2 (PF431396), EGFR (AG1478), PI3K/Akt (LY294002/SH-5), and p300 (GR343), or transfection with siRNAs of c-Src, Pyk2, EGFR, p110, Akt, CREB, and p300. Moreover, thrombin-stimulated phosphorylation of c-Src, Pyk2, EGFR, Akt, CREB and p300 was attenuated by their respective inhibitors. These results indicate that thrombin-induced COX-2 expression is mediated through PAR-1/c-Src/Pyk2/EGFR/PI3K/Akt linking to CREB and p300 cascades. Functionally, thrombin-induced hypertrophy and ANF/BNP release were, at least in part, mediated through a PAR-1/COX-2-dependent pathway. We uncover the importance of COX-2 regarding human cardiomyocyte hypertrophy that will provide a therapeutic intervention in cardiovascular diseases.
authors: Graduate Institute of Biomedical Sciences, Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan; Department of Physiology and Pharmacology, Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors: Peter Tzu-Yu
authors: PT
authors: Chien
authors: Department of Anesthetics, Chang Gung Memorial Hospital at Lin-Kou and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors: Chih-Chung
authors: CC
authors: Lin
authors: Department of Anesthetics, Chang Gung Memorial Hospital at Lin-Kou and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
authors: Li-Der
authors: LD
authors: Hsiao
authors: Graduate Institute of Biomedical Sciences, Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan; Department of Physiology and Pharmacology, Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan. Electronic address: chuenmao@mail.cgu.edu.tw.
authors: Chuen-Mao
authors: CM
authors: Yang
mesh_terms: D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051418:Focal Adhesion Kinase 2; D016392:Proto-Oncogene Proteins pp60(c-src); C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin
keywords: COX-2; CREB; Cardiac hypertrophy; Primary human ventricular cardiomyocyte; Thrombin