Endothelin-1 (ET-1) is a critical molecule that involved in heart failure. It has been proved that ET-1 stimulation results in cardiac hypertrophy both in vitro and in vivo, but the mechanisms underlying remain largely unknown. In this study, we reported that cyclooxygenase-2 (COX-2) might be an important mediator of hypertrophic responses to ET-1 stimulation. In the cultured rat neonatal cardiomyocytes, ET-1 significantly upregulated the expression and activity of COX-2, which was accompanied by increase in cell surface area and BNP mRNA level. In contrast, ET-1-dependent cardiomyocyte hypertrophy was abolished by COX-2 selective inhibitors, NS-398 and celecoxib, or by COX-2 RNA interference, but the inhibitory effects could be diminished by pretreatment with PGE2. Furthermore, cyclosporin A (CsA) and knockdown of nuclear factor of activated T-cells c3 (NFATc3) inhibited the expression of COX-2 induced by ET-1, and NFATc3 could also bound to the -GGAAA- sequence in the promoter region of rat COX-2 gene, indicating that calcineurin/NFATc3 signaling participated in the transcriptional regulation of COX-2 following ET-1 treatment. These findings provided further insight into the roles of ET-1 in cardiac hypertrophy and suggested a potential therapeutic strategy against cardiac hypertrophy by inhibiting COX-2.
Keywords: ANF; AngII; BNP; COX-2; Cardiac hypertrophy; CsA; ET-1; ETAR; ETBR; NF-κB; NFATc3; NFATc4; NRCMs; PGE(2); PGs; angiotenin II; atrial natriuretic factor; brain natriuretic peptide; cyclooxygenase-2; cyclosporin A; endothelin subtype A receptor; endothelin subtype B receptor; endothelin-1; neonatal rat cardiomyocytes; nuclear factor of activated T cells c3; nuclear factor of activated T cells c4; nuclear factor-kappa B; prostaglandin E2; prostaglandins.
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