Human Cardiac Hypertrophy Induced by Thrombin/COX‐2 is Mediated Through a c‐Src/Pyk2/EGFR/CREB‐dependent Pathway

Abstract

Thrombin and cyclooxygenase-2 (COX-2) are elevated, and regulate several inflammatory situations via modulating complex signaling cascades, which participates in many cardiovascular diseases. It has been presented that thrombin induces COX-2 expression through a PAR (protease- activated receptor)-1-dependent manner. The aim of this study was to identify whether thrombin-induced COX-2 expression and prostaglandin E2 (PGE2) release was mediated via a c-Src-dependent transactivation of epidermal growth factor receptor (EGFR) pathway in primary human cardiomyocytes. First, the data showed that thrombin-induced COX-2 promoter activity, mRNA and protein expression, and PGE2 synthesis was prohibited by pretreatment with the pharmacological inhibitors of c-Src, Pyk2, EGFR, PI3K/Akt, and p300, or transfection with siRNAs of c-Src, Pyk2, EGFR, p110, Akt, CREB, and p300. Next, thrombin stimulated activation of phosphorylation of c-Src, Pyk2, EGFR, Akt, MAPKs, and then in turn activated CREB and p300, all of which were repressed by their respective inhibitors. Thrombin-induced COX-2 expression and PGE2 generation is mediated through PAR-1/c-Src/Pyk2-mediated EGFR/PI3K/Akt/MAPKs linking to CREB and p300 cascades. Functionally, thrombin magnified cell hypertrophy and atrial natriuretic factor (ANF) release via these signaling components. Understanding the mechanisms of COX-2 expression by thrombin/PAR-1 system provides a rational therapeutic intervention regarding cardiovascular diseases.