title: COX-2 is involved in ET-1-induced hypertrophy of neonatal rat cardiomyocytes: role of NFATc3.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China.
authors.forename: Si
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Feng
authors.affiliation: Guangzhou Research Institute of Snake Venom, Guangzhou Medical College, Guangzhou 510182, Guangdong, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China. Electronic address: chshaor@mail.sysu.edu.cn.
authors.forename: Shaorui
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou 510006, Guangdong, PR China. Electronic address: liupq@mail.sysu.edu.cn.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D019332:Endothelin-1; D050778:NFATC Transcription Factors; D009578:Nitrobenzenes; D011720:Pyrazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013449:Sulfonamides; C495963:natriuretic peptide precursor type B, rat; D020097:Natriuretic Peptide, Brain; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016572:Cyclosporine; D051546:Cyclooxygenase 2; D019703:Calcineurin; D000068579:Celecoxib; D015232:Dinoprostone
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