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Na+/H+ exchanger isoform 1 induced osteopontin expression in cardiomyocytes involves NFAT3/Gata4

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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.

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Abbreviations

NHE1:

Na+/H+ exchanger isoform 1

OPN:

Osteopontin

NFAT:

Nuclear factor of activated T-cells

ANP:

Atrial natriuretic peptide

ERK:

Extracellular signal regulated kinase

Ang II:

Angiotensin II

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Acknowledgments

This work was supported by the National Priorities Research Program (NPRP 5-330-3-090) grant provided by the Qatar National Research Fund (Doha, Qatar). Mrs. Amy Barr (University of Alberta, Edmonton, Alberta, CA) was generous enough to assist in the preparation, precipitation, purification, and determination of viral titer of the green fluorescent protein (GFP), active NHE1 and OPN adenoviruses.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. College of Pharmacy, Qatar University, P.O. Box 2713, Doha, Qatar

    Mohamed Mlih, Nabeel Abdulrahman, Iman A. Mohamed, Maiy Jaballah & Fatima Mraiche

  2. INSERM U441, Bordeaux, France

    Alain-Pierre Gadeau

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  1. Mohamed Mlih
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  2. Nabeel Abdulrahman
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Correspondence to Fatima Mraiche.

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Mlih, M., Abdulrahman, N., Gadeau, AP. et al. Na+/H+ exchanger isoform 1 induced osteopontin expression in cardiomyocytes involves NFAT3/Gata4. Mol Cell Biochem 404, 211–220 (2015). https://doi.org/10.1007/s11010-015-2380-8

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