Mlih Mohamed, Abdulrahman Nabeel, Gadeau Alain-Pierre, Mohamed Iman A, Jaballah Maiy, Mraiche Fatima
College of Pharmacy, Qatar University, P.O. Box 2713, Doha, Qatar.
Mol Cell Biochem. 2015 Jun;404(1-2):211-20. doi: 10.1007/s11010-015-2380-8. Epub 2015 Mar 11.
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.
骨桥蛋白（OPN）是一种多功能糖磷蛋白，据报道其有助于心脏重塑和肥大的发展及进程。心脏特异性OPN基因敲除小鼠可免受血管紧张素II介导的肥大和纤维化影响。最近，表达钠氢交换体1（NHE1）活性形式的转基因小鼠出现了与OPN水平升高相关的自发性肥大。活性NHE1诱导OPN表达并导致肥大反应的机制尚不清楚。为验证NHE1活性形式的表达是否诱导OPN，用血管紧张素II（已知的OPN和NHE1诱导剂）刺激心肌细胞。血管紧张素II诱导H9c2心肌母细胞肥大，并增加OPN蛋白表达（151.6±28.19%，P<0.01）和NHE1活性。在存在NHE1抑制剂EMD 87580或钙调神经磷酸酶抑制剂FK506的情况下，血管紧张素II诱导的肥大和OPN蛋白表达有所减轻。此外，我们的结果表明，NHE1的激活诱导NFAT3易位至细胞核，并显著激活转录因子Gata4（NHE1：为对照的149±28%，P<0.05）。FK506可抑制NHE1诱导的Gata4激活。总之，我们的结果表明，NHE1的激活通过激活NFAT3/Gata4和OPN表达来诱导肥大。
