C-Src/Pyk2/EGFR/PI3K/Akt/CREB-activated pathway contributes to human cardiomyocyte hypertrophy: Role of COX-2 induction. (5th July 2015)

• Record Type: Journal Article
• Authors: Chien, Peter Tzu-Yu; Lin, Chih-Chung; Hsiao, Li-Der; Yang, Chuen-Mao
• Is Part Of: Molecular and cellular endocrinology. Volume 409(2015)
• Page Start: 59
• Page End: 72
• Publication Date: 2015-07-05
• Subjects: Thrombin -- Primary human ventricular cardiomyocyte -- COX-2 -- CREB -- Cardiac hypertrophy; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2015.04.005
• Languages: English
• ISSNs: 0303-7207

Abstract

Highlights: We evaluate the effects of thrombin on human cardiomyocytes. Up-regulation of COX-2 mediates thrombin-induced cardiomyocyte hypertrophy. c-Src/Pyk2-dependent EGFR transactivation leads to COX-2 induction by thrombin. Thrombin induces COX-2 expression via activation of CREB and p300. We suggest that PAR-1 may be a potential target for heart failure therapy. Graphical Abstract: 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.