title: Na(+)/H (+) exchanger isoform 1 induced osteopontin expression in cardiomyocytes involves NFAT3/Gata4.
abstract: Osteopontin (OPN), a multifunctional glycophosphoprotein, has been reported to contribute to the development and progression of cardiac remodeling and hypertrophy. Cardiac-specific OPN knockout mice were protected against hypertrophy and fibrosis mediated by Ang II. Recently, transgenic mice expressing the active form of the Na(+)/H(+) exchanger isoform 1 (NHE1) developed spontaneous hypertrophy in association with elevated levels of OPN. The mechanism by which active NHE1 induces OPN expression and contributes to the hypertrophic response remains unclear. To validate whether expression of the active form of NHE1 induces OPN, cardiomyocytes were stimulated with Ang II, a known inducer of both OPN and NHE1. Ang II induced hypertrophy and increased OPN protein expression (151.6 ± 28.19 %, P < 0.01) and NHE1 activity in H9c2 cardiomyoblasts. Ang II-induced hypertrophy and OPN protein expression were regressed in the presence of an NHE1 inhibitor, EMD 87580, or a calcineurin inhibitor, FK506. In addition, our results indicated that activation of NHE1-induced NFAT3 translocation into the nucleus and a significant activation of the transcription factor Gata4 (NHE1: 149 ± 28 % of control, P < 0.05). NHE1-induced activation of Gata4 was inhibited by FK506. In summary, our results suggest that activation of NHE1 induces hypertrophy through the activation of NFAT3/Gata4 and OPN expression.
authors.affiliation: College of Pharmacy, Qatar University, P.O. Box 2713, Doha, Qatar.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mlih
authors.forename: Nabeel
authors.initials: N
authors.lastname: Abdulrahman
authors.forename: Alain-Pierre
authors.initials: AP
authors.lastname: Gadeau
authors.forename: Iman A
authors.initials: IA
authors.lastname: Mohamed
authors.forename: Maiy
authors.initials: M
authors.lastname: Jaballah
authors.forename: Fatima
authors.initials: F
authors.lastname: Mraiche
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics*; D005786:Gene Expression Regulation; D006984:Hypertrophy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D032446:Myoblasts / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D053495:Osteopontin / Q000096:biosynthesis* / Q000235:genetics; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage
chemical_list: D027682:Cation Transport Proteins; D050991:GATA4 Transcription Factor; D050778:NFATC Transcription Factors; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D053495:Osteopontin; D016559:Tacrolimus