Review articleRegulation of the cardiac Na+/H+ exchanger in health and disease
Highlights
► Stimulation of hormone receptor activates the sarcolemmal NHE1. ► Activation of NHE1 leads to increase in intracellular pH and Na+ concentration. ► Ionic changes via NHE1 can initiate cardiac hypertrophy and heart failure. ► We discuss upstream and downstream signaling pathways of NHE1.
Introduction
The plasma membrane Na+/H+ exchanger (NHE) catalyzes acid extrusion by electroneutral ion exchange, using the energy support provided by Na+–K+-ATPase. The housekeeping isoform NHE1 is a key regulator of intracellular pH (pHi), Na+ concentration, and cell volume in virtually all tissues [1]. In cardiac muscles, intracellular acidosis results in Na+-overload via NHE1, followed by a sustained increase in the cytosolic Ca2 + concentration via cardiac Na+/Ca2 + exchanger. In addition, acidosis itself seriously reduces myofibrilar Ca2 + sensitivity, resulting in contractile dysfunction. Therefore, it is important for cardiac muscles to rapidly remove acid load during contraction, particularly under pathological conditions such as ischemia.
NHE1 has also been implicated in cardiac hypertrophy and chronic heart disease. In various diseased animal models, the NHE1 inhibitor had a highly beneficial effect [2]. The involvement of NHE1 in chronic disease is strongly linked to the finding that NHE1 is activated in response to hormones such as endothelin-1 and norepinephrine, as well as mechanical stress like stretching; these factors are all inducers of cardiac remodeling. In studies on NHE1, 2 fundamental questions arise: 1) How is NHE1 regulated? and 2) What does NHE1 regulate? Many upstream and downstream targets of NHE1 have been identified. In this review, we will briefly summarize the basic knowledge on the NHE1 molecule and then report the recent progress on several accessory factors of NHE1, which play critical roles in the regulation of NHE1 activity. Finally, we will discuss the amplification of downstream signaling pathways by NHE1 activation, leading to cardiac remodeling. The structure–function relationship and pathological aspects of this transport system have been extensively reviewed earlier [2], [3], [4], [5], [6], [7], [8], [9]. Interested readers should also refer to these reviews.
Section snippets
Na+/H+ exchanger molecule
In 1989, Sardet et al. first cloned the human Na+/H+ exchanger cDNA by genetic complementation of exchanger-deficient cells [10]. This protein is ubiquitously expressed in all tissues and is now known as NHE1. Since the initial identification of NHE1, 9 isoforms have been discovered, referred to as NHE1–NHE9. NHE1–NHE5 are expressed in the plasma membrane, while NHE6–NHE9 localize to the intracellular membranes such as the Golgi apparatus and endosomes [11]. In contrast to the ubiquitous
Regulation of NHE1
NHE1 is activated in response to various extracellular stimuli. This is thought to occur via the interaction of accessory proteins or bioactive substances with the cytoplasmic domain by a phosphorylation-dependent or phosphorylation-independent mechanism. The cytoplasmic domain of NHE1 has been reported to interact with various proteins, including Ca2 +-binding proteins, protein kinases, phosphatases, and cytoskeletal proteins [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]. In
Involvement of NHE1 in cardiac disease
There is ample evidence suggesting that NHE1 mediates cardiac injuries induced by ischemia-reperfusion [92]. This is based on studies indicating that NHE1 inhibitors such as cariporide [93], eniporide [94] and zoniporide [95] afford significant protection against these injuries in many animal models and in patients undergoing coronary interventions [96], [97]. Evidence that mice lacking the Nhe1 gene are resistant to ischemia-reperfusion injury further supports the potential involvement of NHE1
Downstream signaling leading to cardiac hypertrophy and heart failure
NHE1 is activated in response to various hormones such as endothelin-1 [108], angiotensin II [109], and α1-adrenergic agonists [110], as well as mechanical stimuli like stretching [111], [112], [113], all of which contribute to cardiac remodeling [2], [108], [114]. Stretch-induced NHE1 activation may occur via hormone receptor activation caused by an autocrine–paracrine mechanism [115]. NHE1 couples H+ efflux to Na+ influx under the driving force of a Na+ gradient formed by the Na+-pump.
Conclusion
A large body of evidence has indicated the contribution of NHE1 in cardiac remodeling and heart failure. In Fig. 3, we have summarized the relationship between NHE1 and its upstream and downstream target proteins leading to cardiac hypertrophy. Activation of NHE1 can modulate Ca2 +-dependent prohypertrophic signaling via changes in [Na+]i and pHi. The cytoplasmic domain of NHE1 appears to play 2 important roles in this regulation: 1) regulation of NHE1 activity by receiving upstream input
Acknowledgments
We thank Dr. Yuji Arai for the production of transgenic mice, and Dr. Soichi Takeda for crystal structure determination. We also thank all collaborators who participated in our studies. The studies cited from the authors' group are supported by grants from the Ministry of Health, Labour and Welfare; the Ministry of Education, Culture, Sports, Science and Technology; and the National Institute of Biomedical Innovation.
Conflicts of interest
None.
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