Mohamed Iman A, Mraiche Fatima
College of Pharmacy, Qatar University, Doha, Qatar.
J Cell Physiol. 2015 Sep;230(9):2006-18. doi: 10.1002/jcp.24958.
Cardiac hypertrophy (CH), characterized by the enlargement of cardiomyocytes, fibrosis and apoptosis, contributes to cardiac remodeling, which if left unresolved results in heart failure. Understanding the signaling pathways underlying CH is necessary to identify potential therapeutic targets. The Na(+) /H(+) -exchanger isoform I (NHE1), a ubiquitously expressed glycoprotein and cardiac specific isoform, regulates intracellular pH. Recent studies have demonstrated that enhanced expression/activity of NHE1 contributes to cardiac remodeling and CH. Inhibition of NHE1 in both in vitro and in vivo models have suggested that inhibition of NHE1 protects against hypertrophy. However, clinical trials using NHE1 inhibitors have proven to be unsuccessful, suggesting that additional factors maybe contributing to cardiac remodeling. Recent studies have indicated that the upregulation of NHE1 is associated with enhanced levels of osteopontin (OPN) in the setting of CH. OPN has been demonstrated to be upregulated in left ventricular hypertrophy, dilated cardiomyopathy and in diabetic cardiomyopathy. The cellular interplay between OPN and NHE1 in the setting of CH remains unknown. This review focuses on the role of NHE1 and OPN in cardiac remodeling and emphasizes the signaling pathways implicating OPN in the NHE1-induced hypertrophic response.
心肌肥大（CH）的特征是心肌细胞增大、纤维化和凋亡，它会导致心脏重塑，如果不加以解决，最终会导致心力衰竭。了解CH背后的信号通路对于确定潜在的治疗靶点至关重要。钠氢交换体1型（NHE1）是一种广泛表达的糖蛋白，也是心脏特异性亚型，可调节细胞内pH值。最近的研究表明，NHE1表达/活性增强会导致心脏重塑和CH。在体外和体内模型中对NHE1的抑制表明，抑制NHE1可预防肥大。然而，使用NHE1抑制剂的临床试验已被证明是不成功的，这表明可能有其他因素导致心脏重塑。最近的研究表明，在CH情况下，NHE1的上调与骨桥蛋白（OPN）水平升高有关。OPN已被证明在左心室肥大、扩张型心肌病和糖尿病性心肌病中上调。在CH情况下，OPN与NHE1之间的细胞相互作用仍不清楚。本综述重点关注NHE1和OPN在心脏重塑中的作用，并强调涉及OPN在NHE1诱导的肥大反应中的信号通路。
