Cardiovascular Research

Cardiovascular Research 1999 44(3):462-467; doi:10.1016/S0008-6363(99)00210-2
© 1999 by European Society of Cardiology

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Copyright © 1999, European Society of Cardiology

Na⁺/H⁺ exchange hyperactivity and myocardial hypertrophy

Are they linked phenomena?

Horacio E. Cingolani^*

Centro de Investigaciones Cardiovasculares, La Plata 1900, Argentina

^* Corresponding author. Tel.: +54-221-483-4833; fax: +54-221-425-5861

Received 3 March 1999; accepted 22 April 1999

	1 The Na+/H+ exchanger

Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 
Intracellular pH (pH_i) in the majority of living cells is about 6.8–7.2, considerably more alkaline than that predicted for passive distribution of H⁺ across the cell membrane. For the average membrane potential and for an extracellular pH of 7.4, a pH_i value of 6.4 should be expected if H⁺ were in electrochemical equilibrium. At such a pH_i, metabolism and a variety of other cellular functions would be impaired. The existence of mechanisms extruding H⁺ (or acid equivalents) can explain the maintenance of pH_i well above the equilibrium. The Na⁺/H⁺ exchanger (NHE) is one of these mechanisms and plays a central role in the regulation of pH_i as well as in the control of cell volume and of intracellular Na⁺ concentration ([Na⁺]_i). In addition, the exchanger appears to facilitate the induction of cellular growth and proliferation in response to numerous growth factors. The NHE has been found in virtually all living cells and may be phylogenetically one of the most primitive transport systems. The system catalyses the electroneutral exchange of Na⁺ for H⁺, with a coupled 1:1 stoichiometry. Under physiological conditions, the inwardly directed Na⁺ gradient, which is maintained by the activity of the Na⁺–K⁺-ATPase and the Na⁺/Ca²⁺ exchanger, provides a constant driving force for H⁺ extrusion. According to the electrochemical transmembrane gradients, the NHE should extrude intracellular H⁺ in exchange for extracellular Na⁺ until a pH_i far beyond physiological values (8.2–8.5) is obtained. However, at a pH_i of around 7.1–7.2 the antiporter extrudes only the protons generated by the intermediate metabolism and those leaking into the cell, so that pH_i reaches a steady state value. This pH_i at which the NHE is almost quiescent (preventing the rise to non-physiological values) is called "set-point", and can be shifted to more alkaline pH_i values by various stimuli. A prominent feature of this exchanger is that growth factors induce an increase in the level of phosphorylation of the exchanger protein and the shift of the set point [1]. The shift in pH_i threshold is explained by an increased affinity of the exchanger for intracellular H⁺ at the allosteric modifier site.

Although several isoforms of the NHE have been described, the NHE-1 is the most widely distributed, and is the one found in the heart. In the present brief review we will refer to this particular isoform in relation to myocardial hypertrophy. Readers interested in more general aspects of the NHE should consult the Spotlight Issue of Cardiovascular Research published in early 1995 and the reviews by Fröhlich and Karmazyn [2], by Wakabayashi et al. [3], and by Fliegel and Wang [4].

The primary structure of the human growth factor activatable NHE-1 was determined by molecular cloning [5] and sequential homology analysis revealed that this exchanger is a phosphorylated glycoprotein of about 815 aminoacids. NHE has 12 transmembrane spanning domains and both the N- and C-terminal ends are cytoplasmic. The C-terminal end represents a large cytoplasmic domain involved in the regulation of the exchanger activity. The transmembrane region is responsible for Na⁺ and H⁺ transport. Growth factors that activate receptor tyrosine kinases, such us epidermal growth factor, and those acting through G-protein coupled receptors (i.e. thrombin), increase the phosphorylation of the antiporter temporally in parallel with the rise in pH_i [1]. The stimulated phosphorylation occurs exclusively at serine residues and phosphopeptide patterns are the same regardless of the different growth factor in use [1].

The steady-state myocardial pH_i in the absence of bicarbonate (when the only active mechanism is the NHE) is a little bit lower than when bicarbonate is present in the media [6]. The fact that the presence of bicarbonate causes a slight increase in pH_i makes evident that bicarbonate-dependent alkalizing mechanisms also participate on the regulation of pH_i. The Na⁺/HCO₃^– cotransport (NBC) is the most important bicarbonate-dependent alkalizing mechanism, sharing with the NHE the function of keeping pH_i above electrochemical equilibrium. Another important bicarbonate-dependent mechanism is the acidifying Na⁺-independent Cl^–/HCO₃^– exchanger (AE). The activity of the AE increases at pH_i above normal [7]. It should be stressed that both of the alkaline loading mechanisms transport Na⁺ into the cytosol, whereas AE activity does not involve any movement of this ion. Therefore if there is an increase in the activity of one or both of these two alkaline loaders (NHE or NBC), the deviation of pH_i could be compensated by an increase in AE activity but the elevation in [Na⁺]_i will not be corrected.

	2 NHE activity and hypertension

Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 
The enhancement of NHE activity has been described in a substantial variety of cell types obtained from essential hypertensive patients and from animals with experimental forms of hypertension. It is widely accepted that an increased sodium–lithium countertransport can be found in red cells of a variable proportion of patients with essential hypertension (see for review [8]). Although there are some discrepancies about being NHE and sodium–lithium exchange the same mechanism, transfection experiments in Xenopus laevis oocytes suggested that NHE and sodium–lithium countertransport are mediated by the same transport system [9]. One unresolved problem is to ascertain whether the increased intracellular Ca²⁺ concentration ([Ca²⁺]_i) found in hypertensive patients is the result of an enhanced activity of the NHE. The hyperactivity of this exchanger may lead to an increase in [Na⁺]_i which in turn can produce cytoplasmic Ca²⁺ accumulation through the Na⁺/Ca²⁺ exchanger. However, an elevated [Ca²⁺]_i could be responsible for the increased NHE activity through phosphorylation dependent or independent pathways [3]. Data of increased NHE activity have been also collected in skeletal muscle and in circulating blood cells such as platelets, leukocytes and erythrocytes derived from individuals with primary hypertension. Also, increased NHE activity was reported in platelets, lymphocytes, renal tubule cells, and skeletal, smooth vascular and myocardial muscle cells from the genetic model of spontaneously hypertensive rats.

	3 NHE, cellular growth and angiotensin II (Ang II)

Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 
Often, one of the earliest responses to mitogenic or growth signals is a rise in pH_i. The first knowledge about this phenomenon came from studies on the fertilization process of the sea urchin eggs (interested readers see [10]). In these eggs, a large amount of acid is extruded from the cytoplasm after fertilization. The acid extrusion is suppressed by inhibitors of NHE activity and by sodium deprived seawater.

In 1983, Moolenaar et al. suggested that growth factors might, at least in part, stimulate cell growth by increasing pH_i [11]. They showed that the increase in pH_i was caused by the stimulation of the NHE [11]. Later on, in 1989 Boron and his colleagues showed that, if the experimental solution contained bicarbonate and CO₂, not only there was no increase in pH_i but the opposite (a decrease) could take place [12]. Growth factors, in their experimental conditions, stimulated more the acidifying bicarbonate transporter than the NHE. In connection with this, we have reported that easily detected Ang II-induced increase in myocardial pH_i in HEPES, was no longer observed in the presence of bicarbonate. The acidifying AE was simultaneously stimulated by Ang II [13]. Fig. 1 shows the different effect of Ang II on myocardial pH_i depending on the presence of bicarbonate in the media.

View larger version (7K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Angiotensin II-induced stimulation of NHE activity causes the increase in pHi only when there is no bicarbonate in the media. In the presence of the physiological buffer, the expected intracellular alkalization may even turn into a slight acidification. The decrease in pHi could result from overcompensation for the enhanced NHE activity by the acidifier bicarbonate-dependent mechanism (modified with permission from Circ Res. 1998;82:473–481).

 
Perhaps, most of the discrepancies about being pH_i a growth signal arise from thinking that an increase in NHE mandatory implies intracellular alkalization. NHE can be hyperactive and no change in pH_i be detected when a bicarbonate dependent acidifying mechanism, like the AE, is compensating. Growth factors under physiological conditions allow dissociating NHE activity from increases in pH_i. The possibility that changes in pH_i taking place in some organelles and/or cellular compartments cannot be ruled out. Furthermore, in long lasting experiments following changes in pH_i as a function of time are lacking and could be interesting to analyze possible transitory changes that could trigger different mechanisms. In any case, Ang II enhances the activity of the NHE though there is no increase in pH_i in the media with bicarbonate.

	4 Mechanism of Ang II-induced activation of NHE

Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 
The mechanism by which Ang II activates the NHE is complex and, at present, incompletely understood. Even the possibility exists that Ang II could activate the NHE through the release of endogenous endothelin (ET) [14]. In any case, either Ang II or ET seems to activate NHE through a protein kinase C (PKC)-dependent pathway. This conclusion is based on the fact that if PKC is inhibited by chelerythrine, Ang II is no longer inducing an increase in pH_i in the absence of bicarbonate [15].

Most of Ang II actions on the cardiovascular system, including the activation of NHE [16], are mediated through the Ang II type 1 receptor (AT₁R). The AT₁R belongs to the seven transmembrane domain class of receptors coupled to G regulatory proteins. Their activation involves a cascade of events including stimulation of phospholipase C, hydrolysis of phosphatidylinositol 4,5 biphosphate, formation of inositol 1,4,5-triphosphate and diacylglycerol, and activation of PKC. It is very interesting that in experiments of molecular biology of the NHE, a potential PKC consensus phosphorylation site at serine 648 was identified [5]. However, replacement of this serine residue with alanine caused no significant reduction of cytoplasmic alkalization in response to thrombin and phorbol esters [17]. This probably suggests that PKC does not directly phosphorylate the NHE molecule itself, and that other(s) kinases or even a putative regulatory protein [17] phosphorylated by PKC can be the modulators of the antiporter activity.

The role played by Ang II type 2 receptor (AT₂R) in the regulation of NHE activity is unknown. However, preliminary experiments suggested that this subtype of receptors could counteract the stimulation of the NHE mediated by AT₁R [18]. Furthermore, the AT₂R has been shown to increase the activity of phosphatases [19]. The potential role played by AT₂R in the regulation of myocardial pH_i could be important if we consider that AT₂R are up-regulated in the hypertrophied myocardium [20,21].

	5 The link between myocardial strain and hypertrophy

Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 
Elegant experiments conducted in neonatal rat cardiomyocytes cultured on deformable silicone dishes were able to demonstrate the fact that cell stretch results in the activation of multiple signal transduction pathways that are followed by the appearance of the hypertrophied phenotype [22,23]. Interestingly, this stretch response was shown to involve autocrine–paracrine mechanisms because the effect of stretch could be mimicked when the media surrounding the stretched-myocytes was transferred to non-stretched myocytes [22]. Using the same experimental approach, Takewaki et al. demonstrated an elevation of NHE-1 mRNA levels in cardiomyocytes 24 h after stretching [24]. The authors also reported a stretch-induced activation of MAP kinase and that this activation was reduced by approximately 25% with an inhibitor of the NHE activity [24].

In papillary muscles from adult cats we have recently shown that myocardial stretch causes the stimulation of NHE activity through an autocrine–paracrine mechanism in which the AT₁R, ET type A receptor (ET_AR), and PKC-dependent pathways are involved [14]. Fig. 2 schematically represents the hypothetical chain of events that mechanical stretch would evoke in myocardium.

View larger version (16K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Hypothetical diagram of the signalling pathway evoked by mechanical stretch in myocardium. Myocardial stretch induces the release of angiotensin II (Ang II) that acting through AT1 receptors activates protein kinase C (PKC) which, in turn, produces endothelin (ET) release. ET, activating ETA receptors, causes new activation of PKC (another isoform?). PKC phosphorylates and activates a number of different kinases, possibly one specific for the NHE that will activate this exchanger. Some of these kinases will also translocate to the nucleus and phosphorylate transcription factors promoting cell growth. Evidences for this hypothetical model comes from multicellular preparations, so it cannot be ruled out that ET comes from cells other than cardiomyocytes, like endothelial cells. This mechanism constitutes an autocrine–paracrine system in which Ang II and ET are steps in the chain of events.

 
Then, others’ and our experiments strongly suggest that cardiac overload might increase the levels of Ang II at the biophase of receptors. Myocardial pH_i is an intracellular marker of the multiple signals that follow AT₁R activation. The rise in pH_i might be an epiphenomenon of the complex intracellular pathway trigger by growth factors. We should remember that under physiological conditions in which bicarbonate is present, the autocrine–paracrine pathway induces minimal changes in pH_i due to the simultaneous activation of the acid extruder and acid loader mechanisms. However, we should emphasize that the activity of the AE will not prevent the intracellular accumulation of Na⁺caused by the activation of the NHE, which in turn may lead to an increase in [Ca²⁺]_i through the Na⁺/Ca²⁺ exchanger.

An attractive hypothesis will be that the augmented levels of Ang II acting on AT₁R induce intracellular signals that will translocate PKC. PKC activation will induce ET release. This hypothesis, however, can be challenged by recent data showing no difference in membrane fraction of PKC between normal and hypertrophied rat myocardium [25]. The already mentioned enhanced activity of NHE in hypertrophied myocardium might explain the failure of exogenous Ang II to further activate the exchanger in the hypertrophied myocardium [26].

	6 NHE activity and hypertrophied myocardium

Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 
The association between enhanced NHE activity in red blood cells and cardiac hypertrophy in patients with essential hypertension was described by several authors. However, and since only a variable proportion of hypertensive patients show sodium–lithium countertransport abnormalities in blood cells, de la Sierra et al. conducted a prospective study with the aim of detecting a relationship between cardiac hypertrophy and enhanced NHE activity [27]. They showed that only those hypertensive patients with elevated sodium–lithium transport exhibited cardiac hypertrophy [27]. The enhancement of the NHE activity in the hypertrophied myocardium of the spontaneously hypertensive rats was described by our laboratory [28] as well as by others [29]. Enhanced NHE activity might result from increased expression of the transporter protein and/or increased turnover rate of each unit. Although it was described that NHE-1 mRNA levels increased during the development of aortic banding cardiac hypertrophy in rabbits [24], several pieces of evidence would indicate that posttranslational mechanisms, like increased phosphorylation, could be playing the most important role [30]. Our results shown in Fig. 3 are supporting this hypothesis. After the inhibition of PKC, the elevated steady-state pH_i value of hypertrophied myocardium in the absence of bicarbonate returned to normal, suggesting a change in the set point of the NHE [31]. Similar findings were obtained with NHE inhibition [31]. In agreement with this, NHE-1 has been found to be more phosphorylated in SHR vascular smooth muscle cells than in WKY [32].

View larger version (8K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 In the absence of the physiological bicarbonate buffer, the enhanced NHE activity of the hypertrophied myocardium causes steady-state pHi value to be more alkaline than in normal myocardium. Inhibition of NHE activity with EIPA (left side of the figure) resulted in a significant decay of pHi value in the hypertrophied myocardium of spontaneously hypertensive rats (SHR). Consequently, the difference between SHR and Wistar-Kyoto (WKY) rats progressively vanished. The bar in the right of the plot shows the steady-state myocardial pHi of WKY (redrawn with permission from [27]). Interestingly, specific inhibition of PKC activity with chelerythrine (right side) also cancelled the differences in steady-state myocardial pHi values between SHR and WKY (again the bar illustrates pHi in WKY) Figure redrawn with permission from [30]. The normalization of myocardial pHi in SHR by chelerythrine suggests a PKC-mediated pathway as the mechanism that enhances NHE activity, although it not necessary means a dephosphorylation of the exchanger protein itself. The phosphorylation of a putative regulatory protein has been also proposed as responsible for increasing NHE activity in response to PKC activation.

 

	7 Effect of antihypertensive treatments on NHE activity

Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 
We already mentioned that the hypertrophied myocardium of SHR shows enhanced activity of NHE [28,29]. We will briefly review the effect of antihypertensive treatments on cardiac hypertrophy and NHE activity. In 1993 Rosskopf et al. intended to study the effect of the administration of an ACE inhibitor on the enhanced NHE activity of platelets of hypertensive patients [33]. The authors were unable to show significant differences after 6 weeks of treatment with enalapril. Sanchez et al., however, reported the normalization of sodium–lithium countertransport in the erythrocytes of hypertensive patients after 6 months of enalapril treatment [34]. We recently reported that the enhanced activity of the NHE in the hypertrophied myocardium of the spontaneously hypertensive rat was normalized after the chronic administration of enalapril [31]. Preliminary experiments from our laboratory would indicate that normalization of NHE activity in the hypertrophied myocardium could also be obtained after the treatment with an AT₁R antagonist [35]. Whether the normalization of NHE activity is an epiphenomenon or has a causal link with the regression of cardiac hypertrophy deserves further study.

	8 Conclusions

Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 
NHE activity is augmented in the hypertrophied myocardium [28,29]. This is reflected by the increase in the steady-state pH_i value only in the absence of bicarbonate. The pH_i of the hypertrophied myocardium is normalized by both NHE and PKC inhibition, and also after chronic treatment with an ACE inhibitor [31] or AT₁R antagonist [35]. Ang II, in the absence of bicarbonate, induces a PKC-dependent increase in pH_i. When bicarbonate is present the increase in pH_i is offset by the simultaneous activation of the acidifying AE. The stretch of cardiac muscle mimics the action of Ang II on myocardial pH_i.

The modification of NHE activity is an important marker of the intracellular signals accompanying Ang II stimulation and hypertrophy. The fact that the changes in pH_i cannot be detected under physiological conditions suggests that the level of NHE activity, and not the increase in pH_I, is linked to myocardial hypertrophy. The enhanced activity of the NHE will be followed by an increase in [Na⁺]_i and probably in [Ca²⁺]_i, although no changes in pH_i occur.

An attractive hypothesis would be that the stretch of cardiac muscle, acting through an autocrine–paracrine mechanism, induces the release of Ang II that in turn causes synthesis and/or release of ET. The possible involvement of ET in cardiac hypertrophy has already been suggested [25]. ET will activate PKC and this will initiate a cascade of reactions leading to phosphorylation of several other kinases, including perhaps a specific kinase of the NHE that has been already described in vascular smooth muscle [36]. NHE activity, then, becomes a marker of the antiporter state of phosphorylation regulated by kinases. The concept that the increase in pH_i is a growth signal is being challenged by our own results in myocardium [13] and those of Ganz et al. in mesangial cells showing that the increase in pH_i after Ang II may turn into acidification in the presence of bicarbonate [12].

We would like to emphasize that the hyperactivity of the NHE is connected with an increase in pH_i only if it is not compensated by simultaneous hyperactivity of the acidifying AE. Actually, this is the case in the hypertrophied myocardium of the rat. The lack of bicarbonate in many experiments was perhaps the reason to postulate the increase in pH_i as a growth signal. Therefore, the increase in NHE activity but not the rise in pH_i seems to be linked to growth.

Which is the link between the activity of the NHE and growth? A variety of mechanical and pharmacological stimuli leading to cardiac hypertrophy concomitantly activate kinases and NHE. Under physiological conditions (bicarbonate in the media), the activation of the antiporter is not accompanied by a rise in pH_i because it is being compensated by the hyperactivity of the AE; however, [Na⁺]_i does increase. The two events, NHE activation and hypertrophy, may lay on parallel pathways sharing common upstream elements. The increased activity of the NHE seems to be therefore, a ‘marker’ of the activation of those kinases that lead to myocardial hypertrophy.

Time for primary review 22 days.

	Acknowledgements

 
The author thanks Drs. Marìa C Camilión de Hurtado, Irene L Ennis and Bernardo V Alvarez for their help in preparing this manuscript.

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Top 1 The Na+/H+ exchanger 2 NHE activity and... 3 NHE, cellular growth... 4 Mechanism of Ang... 5 The link between... 6 NHE activity and... 7 Effect of antihypertensive... 8 Conclusions References

 

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				X. T. Gan, V. Rajapurohitam, J. V. Haist, P. Chidiac, M. A. Cook, and M. Karmazyn Inhibition of Phenylephrine-Induced Cardiomyocyte Hypertrophy by Activation of Multiple Adenosine Receptor Subtypes J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 27 - 34. [Abstract] [Full Text] [PDF]

				S. M Pogwizd, K. R Sipido, F. Verdonck, and D. M Bers Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis Cardiovasc Res, March 15, 2003; 57(4): 887 - 896. [Full Text] [PDF]

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