c-Src/Pyk2/EGFR/PI3K/Akt/CREB-activated pathway contributes to human cardiomyocyte hypertrophy: Role of COX-2 induction

Mol Cell Endocrinol. 2015 Jul 5:409:59-72. doi: 10.1016/j.mce.2015.04.005. Epub 2015 Apr 11.

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.

Keywords: COX-2; CREB; Cardiac hypertrophy; Primary human ventricular cardiomyocyte; Thrombin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 / metabolism*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Focal Adhesion Kinase 2 / genetics
  • Focal Adhesion Kinase 2 / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Infant, Newborn
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic / drug effects
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Signal Transduction / drug effects*
  • Thrombin / pharmacology*

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Phosphatidylinositol 3-Kinases
  • EGFR protein, human
  • ErbB Receptors
  • Focal Adhesion Kinase 2
  • Proto-Oncogene Proteins pp60(c-src)
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • Thrombin