title: Na+/H+ exchanger isoform 1-induced osteopontin expression facilitates cardiomyocyte hypertrophy.
abstract: Enhanced expression and activity of the Na+/H+ exchanger isoform 1 (NHE1) has been implicated in cardiomyocyte hypertrophy in various experimental models. The upregulation of NHE1 was correlated with an increase in osteopontin (OPN) expression in models of cardiac hypertrophy (CH), and the mechanism for this remains to be delineated. To determine whether the expression of active NHE1-induces OPN and contributes to the hypertrophic response in vitro, cardiomyocytes were infected with the active form of the NHE1 adenovirus or transfected with OPN silencing RNA (siRNA-OPN) and characterized for cardiomyocyte hypertrophy. Expression of NHE1 in cardiomyocytes resulted in a significant increase in cardiomyocyte hypertrophy markers: cell surface area, protein content, ANP mRNA and expression of phosphorylated-GATA4. NHE1 activity was also significantly increased in cardiomyocytes expressing active NHE1. Interestingly, transfection of cardiomyocytes with siRNA-OPN significantly abolished the NHE1-induced cardiomyocyte hypertrophy. siRNA-OPN also significantly reduced the activity of NHE1 in cardiomyocytes expressing NHE1 (68.5±0.24%; P<0.05), confirming the role of OPN in the NHE1-induced hypertrophic response. The hypertrophic response facilitated by NHE1-induced OPN occurred independent of the extracellular-signal-regulated kinases and Akt, but required p90-ribosomal S6 kinase (RSK). The ability of OPN to facilitate the NHE1-induced hypertrophic response identifies OPN as a potential therapeutic target to reverse the hypertrophic effect induced by the expression of active NHE1.
authors.affiliation: College of Pharmacy, Qatar University, Doha, Qatar.
authors.forename: Iman A
authors.initials: IA
authors.lastname: Mohamed
authors.affiliation: University of Bordeaux, Adaptation Cardiovasculaire à L'ischémie, UMR1034, Pessac, France.
authors.forename: Alain-Pierre
authors.initials: AP
authors.lastname: Gadeau
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Larry
authors.initials: L
authors.lastname: Fliegel
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Lopaschuk
authors.affiliation: College of Pharmacy, Qatar University, Doha, Qatar.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mlih
authors.affiliation: College of Pharmacy, Qatar University, Doha, Qatar.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Abdulrahman
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Fillmore
authors.affiliation: College of Pharmacy, Qatar University, Doha, Qatar.
authors.forename: Fatima
authors.initials: F
authors.lastname: Mraiche
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049108:Cell Enlargement; D002478:Cells, Cultured; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D053495:Osteopontin