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Research ArticleCardiovascular

Characterization of Stressed Transgenic Mice Overexpressing H2-Histamine Receptors in the Heart

Ulrich Gergs, Uwe Kirchhefer, Fabian Bergmann, Bernhard Künstler, Natascha Mißlinger, Bastian Au, Mareen Mahnkopf, Hartmut Wache and Joachim Neumann
Journal of Pharmacology and Experimental Therapeutics September 2020, 374 (3) 479-488; DOI: https://doi.org/10.1124/jpet.120.000063

Abstract

We studied transgenic mice with cardiac-specific overexpression of H2-histamine receptors (H2-TG) by using the α-myosin heavy-chain promoter. We wanted to address whether this overexpression would protect the heart against paradigmatic stressors. To this end, we studied isolated atrial preparations in an organ bath under normoxic and hypoxic conditions and after prolonged exposure to high histamine concentrations. Moreover, we assessed cardiac function using echocardiography in mice with cardiac hypertrophy due to overexpression of the catalytic subunit of PP2A (PP2A-TG) in the heart [H2-TG × PP2A-TG = double transgenic (DT)] or H2-TG with cardiac systolic failure due to treatment of mice with lipopolysaccharides (LPSs). Furthermore, the effect of ischemia and reperfusion was studied in isolated perfused hearts (Langendorff mode) of H2-TG. We detected evidence for the protective role of the overexpressed H2-histamine receptors in the contractile dysfunction of DT and isolated atrial preparations subjected to hypoxia. In contrast, we noted the detrimental role of H2-histamine receptor overexpression against ischemia (Langendorff perfusion) and LPS-induced systolic heart failure. Hence, the role of H2-histamine receptors in the heart is context-sensitive: the results differ between hypoxia (in atrium) and ischemia (perfused whole heart), as well as between genetically induced hypertrophy (DT) and toxin-induced heart failure (LPS). The underlying molecular mechanisms for the protective or detrimental roles of H2-histamine receptor overexpression in the mammalian heart remain to be elucidated.

SIGNIFICANCE STATEMENT The beneficial and detrimental effects of the cardiac effects of H2-histamine receptors in the heart under stressful conditions, here intended to mimic clinical situations, were studied. The data suggest that depending on the clinically underlying cardiac pathophysiological mechanisms, H2-histamine agonists or H2-histamine antagonists might merit further research efforts to improve clinical drug therapy.

Introduction

An important monoamine, histamine [imidazolyl-ethylamine or 2-(1H-imidazol-4-yl)ethanamine; review: Parsons and Ganellin (2006)], can mediate many pathophysiological processes, including inflammation, allergies, and responses to stress in the widest sense (Jutel et al., 2009). Histamine was first synthesized by Windaus and Vogt (1907) from imidazolylpropionic acid in vitro. Ackermann (1910) showed that bacteria could convert histidine to β-imidazolyl-ethylamine, which was later called histamine (Fühner, 1912).

Dale and Laidlaw (1911) and subsequent papers from Sir Dale’s group in Oxford (England) were the first to describe the presence, synthesis, and degradation of histamine in mammalian tissue and a possible role of histamine as a transmitter in the cardiovascular system and the putative role of histamine in cardiac anaphylaxis; they noted that histamine exerted positive chronotropic effects and positive inotropic effects not only in the spontaneously beating Langendorff heart of rabbits but also in rabbits in vivo (Dale and Laidlaw, 1911).

We recently overexpressed the H2-histamine receptor in the heart using the α-myosin promoter. This promoter drives the expression in all cells that physiologically contain α-myosin. In other words, we overexpressed the H2-histamine receptor in cardiomyocytes specifically. We (Gergs et al., 2019) published an entire extensive report on the cardiac phenotype of this H2-histamine receptor–overexpressing mouse (H2-TG) compared with its wild-type (WT) littermates. In brief, only in H2-TG, but not in WT, did histamine increase the force of contraction and the beating rate (Gergs et al., 2019). This was seen in isolated atrial preparations, isolated electrically driven cardiomyocytes, Langendorff perfused hearts, and in vivo using echocardiography (Gergs et al., 2019). Using autoradiography with a ligand for the H2-histamine receptors, we could localize the overexpressed receptor to the atrium and the ventricle of H2-TG (Gergs et al., 2019).

In the present study, we used this model to address the possible protective or detrimental role of H2-histamine receptors in the mammalian heart under stressful conditions. In the present context, it is important to keep in mind that histamine has failed to exert any cardiac effects in isolated tissue or living WT mice (Gergs et al., 2019). Hence, the present model offers a unique opportunity to study the human H2-histamine receptor in a mammalian cardiac model using WT mice as a negative control.

During myocardial infarction, the plasma levels of histamine greatly increase in men and mice [Chen et al., 2017, review: Reid et al. (2011)]. Histamine is also released from isolated saline buffer–perfused ischemic hearts (Genovese et al., 1988). In various models of sepsis, an increase of histamine in plasma has been found; for instance, lipopolysaccharide (LPS, a model of Gram negative bacteria–mediated sepsis) was intraperitoneally injected in rabbits (Matsuda et al., 2002) and in mice (Yokoyama et al., 2004) and led to elevated histamine levels in the plasma.

Elevated histamine levels might be protective because histamine injections can increase the survival rate of LPS-treated mice (Yokoyama et al., 2004). These high levels of histamine, on the other hand, might lead to receptor desensitization: one of the earliest reports on desensitization of H2-histamine receptors was in human T-lymphocytes (Schreurs et al., 1984), with later evidence suggesting that this desensitization of the H2-histamine receptor involves protein kinases (Fernández et al., 2002, 2011).

Firm evidence indicates that H2-histamine receptors can play a role in cardiomyopathy and heart failure; for instance, in a dog model, cardiomyopathy (pacing-induced tachycardia leading to cardiac hypertrophy over time) was ameliorated by giving an H2-histamine receptor antagonist (Takahama et al., 2010). In the H2-histamine receptor knockout mice, aortic banding led to less cardiac fibrosis than in sham-operated mice, which may mean that under these conditions, H2-histamine receptors are detrimental for cardiac function by facilitating cardiac hypertrophy (Zeng et al., 2014).

Generally, the density of mast cells is increased in the hypertrophied heart (Francis and Tang, 2006). At the same time, histamine is highly concentrated in mast cells (Jutel et al., 2009); this may mean that, via mast cells, cardiomyopathy leads to an increase in the availability of putative detrimental histamine in heart tissue.

Hitherto, in the current study, we hypothesized that in H2-TG mice, the H2-histamine receptors are detrimental for cardiac function under pathologic conditions and answered the following questions: Do H2-histamine receptors in the heart protect the heart against ischemic, reperfusion, or hypoxic injury? Do high cardiac levels of histamine (which can occur under pathologic conditions) functionally impair H2-histamine receptor function in the heart? Do H2-histamine receptors in the heart protect the heart against genetic hypertrophy (PP2A mice) or toxin-induced hypertrophy (LPS) and impaired cardiac function? Progress reports of this work have been published previously as congress abstracts (Künstler et al., 2015; Bergmann et al., 2016; Gergs et al., 2016; Neumann et al., 2016, 2017a,b, 2018a,b; Mißlinger et al., 2017; Au et al., 2018).

Materials and Methods

Experimental Animals.

The investigations in the present report conform to the Guide for the Care and Use of Laboratory Animals published by the National Research Council (2011). Animals were maintained and handled according to the approved protocols of the animal welfare committees of the University of Münster, Germany, and of the University of Halle-Wittenberg, Germany. The generation of H2-TG has recently been reported (Gergs et al., 2019), and before the PP2A-TG (Gergs et al., 2004), double transgenic (DT) mice were obtained by crossbreeding these lines (H2-TG × PP2A-TG = DT).

Isolated Atrial Preparations.

Jointly, the contractile studies followed our published procedures (e.g., Gergs et al., 2010, 2019). Mice were anesthetized by an intraperitoneal injection of pentobarbital sodium (50 mg kg−1), and the hearts were excised. The right and left atria were dissected from hearts of H2-TG or littermate wild-type mice and mounted in an organ bath. Left atrial preparations were continuously electrically stimulated (field stimulation) with each impulse; these consisted of 1 Hz, with a voltage 10%–15% above the threshold and a 5-millisecond duration. Right atrial preparations were allowed to contract spontaneously. The bathing solution contained (in mM) NaCl 119.8, KCI 5.4, CaCl2 1.8, MgCl2 1.05, NaH2P04 0.42, NaHCO3 22.6, Na2EDTA 0.05, ascorbic acid 0.28, and glucose 5.0; this was continuously gassed with 95% O2 and 5% CO2 and maintained at 35°C, resulting in a pH of 7.4. Forces of contraction detected via an isometric force transducer were amplified and continuously recorded using a PowerLab system (ADInstruments, Oxford, UK).

The key findings were obtained in isolated left and right atria of mice as reported repeatedly before (e.g., Neumann et al., 1998, Gergs et al., 2019). Briefly, hypoxia was induced by switching the gas supply for 20 minutes to a mixture of 95% N2 and 5% CO2 (obtained from Linde Gas supply, Germany). Thereafter, the gas supply was switched again to carbogen. At the indicated times, the atrium was rapidly frozen to the temperature of liquid nitrogen (−196°C) and stored at −80°C until biochemical analysis (see below). In some experiments, different protocols were used, including hypoxic precondition. Details can be found in the appropriate legends and figures.

Isolated Perfused Hearts.

Langendorff preparations of the mouse hearts were used as described previously (Kirchhefer et al., 2014, Gergs et al., 2019). The mice were anesthetized by intraperitoneal injection of pentobarbital sodium (50 mg kg−1), and the hearts were excised. The hearts were removed from the opened chest, immediately attached by the aorta to a 20-gauge cannula, and perfused retrogradely under a constant flow of 2 ml min−1 with oxygenized buffer solution (37°C) containing (in mM) NaCI 119.8, KCI 5.4, CaCl2 1.8, MgCl2 1.05, NaH2P04 0.42, NaHCO3 22.6, Na2EDTA 0.05, ascorbic acid 0.28, and glucose 5.0 in an isolated heart system built in-house. The heart preparations were allowed to equilibrate for 30 minutes before measurements were taken. Hearts beating spontaneously and left ventricular force were measured and monitored continuously. Ischemia was simulated by stopping the peristaltic pump for the buffer for 20 minutes. Reperfusion was simulated by starting the pump again. At the end of the reperfusion time, whole hearts were frozen by freeze clamping and brought to the temperature of liquid nitrogen (−196°C) by using precooled aluminum (Wollenberger) tongs.

Western Blot Analysis.

Material from atrial or ventricular tissue was homogenized (as described repeatedly in Neumann et al., 1998, Gergs et al., 2019) in 300 µl of 10 mM NaHCO3 and 100 µl 20% SDS. Crude extracts were incubated at 25°C for 30 minutes before centrifugation to remove debris; thereafter, the supernatants (homogenates) were separated and stored at −80°C until further use. Western blot analysis was performed as previously described (Gergs et al., 2004, 2010, 2019). Briefly, aliquots of 100 µg of protein were loaded per lane. Finally, bands were detected using enhanced chemifluorescence (GE Healthcare Europe, Freiburg, Germany) together with a Typhoon 9410 Variable Mode Imager (GE Healthcare Europe). The following primary antibodies were used in the current study: polyclonal rabbit anti-calsequestrin (dilution 1:1000; Acris Antibodies, Hiddenhausen, Germany), monoclonal mouse anti-phospholamban (PLB; A-1, dilution 1:2000; Badrilla, Leeds, UK), polyclonal rabbit anti–phosphoserine-16-PLB (dilution 1:5000; Badrilla), and monoclonal rabbit anti-troponin inhibitor and polyclonal rabbit anti–phosphoserine-23/24 troponin inhibitor (dilution 1:1000; both from Cell Signaling Technology, Frankfurt am Main, Germany). The characteristics and use of these antibodies have been reported repeatedly by our group (Kirchhefer et al., 2002).

Echocardiography.

The echocardiographic measurements in spontaneously breathing mice were performed under anesthesia with 1.5% isoflurane, as described previously (Gergs et al., 2010, 2019).

Sepsis Model.

Intraperitoneal injections of LPS in mice were performed with 30 µg/g body weight. LPS was dissolved in isotonic NaCl solution. The control mice were injected with isotonic NaCl solution.

Data Analysis.

The data shown are means ± S.D. Statistical significance was estimated by an ANOVA followed by Bonferroni t test using Prism 5 (GraphPad Software, San Diego, CA). A P value <0.05 was considered as significant.

Drugs and Materials.

Histamine, dimaprit, and LPS [Escherichia coli (O55:B5)] were purchased from Sigma-Aldrich (Taufkirchen, Germany). All other chemicals were of analytical grade. Demineralized water was used throughout the experiments. Stock solutions were freshly prepared daily.

Results

The quantification of cardiac weight in PP2A-TG (see Fig. 1) detected cardiac hypertrophy [as described before in Gergs et al. (2004)], whereas H2-TG was devoid of an increase in cardiac size (Fig. 1). In DT mice (generated by crossbreeding H2-TG with PP2A-TG), we did not notice a reduction of cardiac weight compared with monotransgenic PP2A-TG mice (Fig. 1).

Fig. 1.
Fig. 1.

PP2A-TG showed an increased relative heart weight (ordinate). Ordinate: relative heart weight (heart weight divided by body weight in milligrams per gram). WT, open circles; H2-TG, closed circles; PP2A-TG, squares; DT, triangles. Numbers in brackets indicate the numbers of animals investigated. +P ˂ 0.05 vs. WT.

Regarding cardiac echocardiography, however, the systolic (Fig. 2) and diastolic cardiac functions were less impaired in DT than in PP2A-TG (Fig. 3). Interestingly, the β-adrenoceptor agonist isoproterenol (isoprenaline) increased systolic function in vivo in all four genotypes, as assessed by measuring the ejection fraction (Fig. 2). However, histamine only increased the ejection fraction in mice in H2-TG or DT (Fig. 2, black bars). Likewise, cardiac dimensions were elevated in PP2A mice and less elevated in DT (Fig. 4, A and B).

Fig. 2.
Fig. 2.

Ejection fraction (EF) of left ventricle after intraperitoneal injection of histamine or isoproterenol. Using echocardiography, histamine (100 µl of 1 mM, i.p.) elevated contractility in H2-TG compared with WT mice. PP2A-TG and DT (H2-TG × PP2A-TG) were less reactive to isoproterenol (100 µl of 10 mM, i.p.). Interestingly, in DT the EF was higher than in PP2A-TG at similar heart rates. ANOVA with Bonferroni post hoc test. +P ˂ 0.05 vs. WT, xP ˂ 0.05 vs. H2-TG, #P ˂ 0.05 vs. PP2A-TG, ⋆P ˂ 0.05 vs. corresponding basal level.

Fig. 3.
Fig. 3.

(A) E′/A′ ratio in DT mice was increased. (B) Representative pulsed wave (PW) tissue Doppler of WT, which marks the S, E′, and A′ waves. S, systolic wave; E wave, mitral peak velocity blood flow in early diastole caused by left ventricular relaxation; A wave, peak velocity blood flow in late diastole caused by atrial contraction. By tissue Doppler, the retrograde waves, E' (passive LV filling) and A'-wave (atrial contraction) can be measured and E'/A' can be used as a marker of diastolic dysfunction, xP ˂ 0.05 vs. H2-TG. WT, open circles; H2-TG, closed circles; PP2A-TG, squares; DT, triangles.

Fig. 4.
Fig. 4.

Overexpression of the catalytic subunit of PP2A in PP2A-TG led to increased systolic and diastolic diameters of the left ventricle. (A) Quantification of echocardiographically measured systolic or diastolic left ventricular (LV) diameters in parasternal long axis view (PLAX). DT (H2-TG × PP2A-TG) seemed to be less affected than PP2A-TG. ANOVA with Bonferroni post hoc test: +P ˂ 0.05 vs. WT, xP ˂ 0.05 vs. H2-TG, #P ˂ 0.05 vs. PP2A-TG. (B) Representative M-mode pictures for all investigated genotypes. Red, systolic diameter; blue, diastolic diameter.

Thereafter, we investigated the effect of global ischemia in isolated buffer-perfused hearts (Langendorff mode) and subsequent reperfusion. The protocol used and typical force tracings can be seen in Fig. 5. Under these conditions, we did not note a protection in H2-TG (Fig. 6). In contrast, there was evidence that the force of hearts from H2-TG deteriorated faster than in WT mouse hearts (Fig. 6C). Moreover, after reperfusion, more time was required to regain sinus rhythm in atria from H2-TG overexpressing mice than in WT (Fig. 6D).

Fig. 5.
Fig. 5.

Typical original recordings of the time course of force reduction (no flow ischemia) and force recovery [reperfusion (Rep)] in isolated perfused heart (Langendorff) preparations from WT and H2-TG. The flow of 2 ml/min was stopped (global ischemia = no flow ischemia) for 20 minutes, as indicated by a horizontal line and restarted at the indicated time point. Ordinate: developed tension in millinewtons.

Fig. 6.
Fig. 6.

A period of 20 minutes of ischemia (see Fig. 5) did not cause permanent damage because, after reperfusion, force (A) and heart rate (B) of both H2-TG and WT reached preischemic values again. Time to 50% decline of developed force (F1/2) during ischemia was reduced in H2-TG compared with WT (C), and after start of reperfusion, time to return to sinus rhythm was prolonged in H2-TG (*two of six preparations did not reach sinus rhythm within 15 minutes) compared with WT (D). Ctr, control perfusion without ischemia. +P < 0.05 vs. WT, n = 6.

Underexposure of the isolated left or right atrium from H2-TG to high bath concentrations of histamine (100 µM, 1 hour) reduced the ability of histamine (Fig. 7, A and B) or the H2-receptor agonist dimaprit (Fig. 7, C and D) to elicit a concentration-dependent positive inotropic effect and a positive chronotropic effect (Fig. 7, E and F), respectively. For comparison, we also found that the pretreatment of whole animals with dimaprit could attenuate the positive inotropic effect and the positive chronotropic effect of dimaprit in vivo (echocardiography: Fig. 8) in H2-TG.

Fig. 7.
Fig. 7.

In vitro desensitization of H2-histamine receptors in isolated electrically driven (1 Hz) left atrial preparations of H2-TG mice. First (see schematic drawing), initial concentration-response curves for histamine or the H2-receptor agonist dimaprit were established. The effect of histamine was completely washed out by repeatedly exchanging the buffer in the organ bath. Thereafter, preparations were incubated with a high concentration of histamine or dimaprit (100 µM) for 1 hour, or no additions were given [nondesensitized (N-DS)]. After complete washout of histamine/dimaprit, a second concentration-response curve for (A) histamine or (C) dimaprit was obtained. (B) EC50 value of histamine; (D) comparison of desensitization (des.) with histamine and dimaprit. Similarly, as in left atria, desensitization was studied in isolated spontaneously beating right atrial preparations comparing histamine (E) and dimaprit (F) as histamine receptor agonists. The positive chronotropic effect (given as beating rate in the ordinates) of H2-receptor stimulation was subject to desensitization by both histamine and dimaprit. Ctr, control data before drug application. Numbers in brackets indicate animals studied. *First P ˂ 0.05 vs. Ctr; #P ˂ 0.05 vs. nondesensitized; +P ˂ 0.05 vs. desensitization with histamine. DS, desensitization.

Fig. 8.
Fig. 8.

In vivo desensitization. Living H2-TG mice were treated intraperitoneally with dimaprit, and echocardiographic responses were studied. After recording basal cardiac parameters and dimaprit-induced cardiac effects, a high dose of dimaprit was injected [saline buffer in control experiments; nondesensitized (N-DS)], and 30 minutes later, dimaprit was injected again. Here, the effects of the third application of dimaprit are shown: (A) changes in heart rate after dimaprit injection and (B) changes in ejection fraction (EF) after dimaprit injection. *P ˂ 0.05 vs. N-DS. Hence, the contractile and chronotropic effects of dimaprit are attenuated after desensitization. DS, desensitization.

As shown in Fig. 9A, the atria of H2-TG are more resistant to hypoxia than the atria from WT (Fig. 9A). This protective effect of transgenicity was abolished by adding the H2-histamine receptor antagonist cimetidine to the organ bath shortly before the induction of hypoxia (Fig. 9B). A similar protective effect of transgenicity was noted after preconditioning of the atria (Fig. 9C).

Fig. 9.
Fig. 9.

Hypoxia in isolated electrically driven (1 Hz) left atrium in the organ bath. (A–D) Representative recordings of WT and H2-TG left atrial preparations demonstrate the experimental design of the study (left-hand sides of panels, respectively). In the diagrams, the force of contraction in % of control (Ctr = initial force at the beginning of the experiment) during the time of reoxygenation is presented. In H2-TG left atria, a better recovery was noted after a single hypoxia compared with WT (A). In presence of cimetidine (10 μM), this effect was absent (B). A preconditioning period (10 minutes of hypoxia) was not beneficial (C). In the presence of histamine (1 μM), the relative force during reoxygenation was greatly increased in H2-TG and reached again the initial force (D). Cim, cimetidine; His, histamine. *P < 0.05 vs. WT.

When stimulating the atria with histamine, the protective effect of transgenicity against hypoxia was greatly increased: only in H2-TG, but not in WT, did histamine quickly elicit a pronounced positive inotropic effect (Fig. 9D). During hypoxia, the force of contraction fell in the atrium from both H2-TG and WT. However, during reoxygenation, the force returned to higher values in the atrium of H2-TG than in WT, but not to prehypoxic levels (Fig. 9D). The phosphorylation states of PLB at serine 16 and the inhibitory protein of troponin were higher in TG than in WT when measured at the end of 30 minutes of reoxygenation under the conditions shown in Fig. 9D.

However, LPS led to a time-dependent decrease in cardiac function (Fig. 10). In some parameters, a decrease in cardiac function was noted as early as 1 hour after injecting LPS. This decrease was more severe in hearts from H2-TG than in WT (Fig. 10). LPS induced the mRNA expression of various genes, such as interleukin-6 and interleukin-1β (data not shown), in these hearts. LPS increased the mRNA expression of tumor necrosis factor α much further in WT than in H2-TG.

Fig. 10.
Fig. 10.

Echocardiographic parameters under simulated sepsis. H2-TG and WT mice were injected with LPS or solvent control (NaCl). Data were collected before [basal (B)] as well as 1, 3, and 7 hours after LPS application. (A) Ejection fraction (EF) measured in the parasternal long-axis (PLAX) view; (B) heart rate; (C) pulmonary arterial flow; (D) cardiac output. Numbers in brackets indicate numbers of animals investigated. ANOVA with Bonferroni post hoc test: ⋆P < 0.05 vs. corresponding NaCl; #P < 0.05 vs. B.

Discussion

As a new contribution to the field, in the present work, we studied the effect of the various stressors of cardiac function in vitro and in vivo in H2-TG—a novel model system (Fig. 11; Gergs et al., 2019) with cardiac-specific expression of a functional human H2-histamine receptor—compared with appropriate control conditions.

Fig. 11.
Fig. 11.

Scheme of a mammalian cardiomyocyte. Histamine in the extracellular space stimulates H2-histamine receptors (H2R). This can lead to increased activity of stimulatory GTP-binding proteins (Gs) and hence increased activity of the adenylyl cyclase (AC). This will increase the level of cAMP, which elevates the activity of cAMP-dependent protein kinases A (PKA). The kinases can increase the phosphorylation state (P) of cardiac regulatory proteins like the L-type calcium ion channel (LTCC), the ryanodine receptor (RyR) in the junctional sarcoplasmic reticulum, and PLB in the free sarcoplasmic reticulum. Phosphorylation of PLB increases the uptake of calcium ions (Ca2+) into the sarcoplasmic reticulum via sarcoplasmic reticulum ATPase (SERCA), where it binds mainly to calsequestrin (CSQ). Protein phosphatases like the catalytic subunit of PP2A (a serine, threonine phosphatase) reverse these phosphorylations. Increases in free cytosolic calcium ion concentrations due to H2-histamine receptor stimulation lead to an increase in force of contraction via action on myofibrils. Under pathophysiological conditions like sepsis, histamine levels can increase in the extracellular space and might desensitize histamine receptors. H2-histamine receptors are typically blocked by cimetidine. LPSs, mediators of bacterial sepsis, can decrease cardiac contractility via action on the toll like receptor 4 complex (CD14/TLR4) on cardiomyocytes and increased levels of cardiac depressant inflammatory mediators.

We have a long-standing interest in cardiac phosphatases, namely serine/threonine phosphatases. We have worked for a long time on how they might contribute to β-adrenergic and muscarinic acetylcholine receptor M2 signaling in the heart (Neumann et al., 1994). Based on our old studies, we have continuously developed new transgenic models for the main serine/threonine phosphatases in the heart. We were interested in not only how they alter the signals leading from the sarcolemmal receptors to the activation of protein kinases but also how they might play a role in the development of cardiac hypertrophy (Boknik et al., 2000) and even heart failure, which we looked at in some initial studies in human hearts (Neumann et al., 1999). In this line, we quite extensively characterized PP2A in humans (Knapp et al., 1999) and animal hearts (Neumann et al., 1993; Gombosova et al., 1998), overexpressed the catalytic subunit of PP2A (Gergs et al., 2004), and studied its role under stressful conditions, such as hypertension-induced hypertrophy (aortic banding) myocardial infarction (Brüchert et al., 2008; Grote-Wessels et al., 2008; Hoehn et al., 2015). Because the H2-histamine receptor mediates its effects via cAMP and protein kinase A and phospholamban phosphorylation (Gergs et al., 2019), it seemed logical to test the influence of PP2A on H2-histamine receptor–mediated effects because PP2A is known to dephosphorylate phospholamban not only in vitro (Neumann et al., 1993) but also in the beating heart (Gergs et al., 2004).

Before, we have reported and confirmed that cardiac-specific overexpression of the catalytic subunit of PP2A leads to cardiac hypertrophy and signs of systolic and diastolic heart failure and impaired cardiac dimensions (Gergs et al., 2004). H2-histamine receptor overexpression in hearts of transgenic mice alone (H2-TG) has been found to be devoid of cardiac hypertrophy or impaired cardiac function to β-adrenoceptor stimulation by isoproterenol (Gergs et al., 2019, and the current report). In the present study, at least diastolic heart failure was reduced in DT compared with PP2A mice. We regard this as an example of the putative protective role of H2-histamine receptors in the heart. One could speculate that this beneficial effect would be seen in patients with elevated histamine levels. The biochemical reasons need to be elucidated: we have shown that overexpression of the catalytic subunit of PP2A leads to dephosphorylation of several cardiac regulatory proteins (PP2A-TG: Gergs et al., 2004), whereas the stimulation of H2-histamine receptors leads to acute increases in the phosphorylation state of cardiac regulatory proteins (H2-TG: Gergs et al., 2019). Therefore, it seems reasonable to hypothesize that H2-histamine receptor overexpression additionally to PP2A overexpression normalizes these phosphorylation states and, thus, cardiac dimensions and function.

Concerning plasma histamine levels, the literature agrees on a substantial increase in this parameter after an experimental induction of sepsis in animal models [such as by LPS used in the present report, reviewed in Matsuda et al. (2002)]. In rats, endotoxin-induced mortality was reduced if (probably by normalizing a decreased blood pressure) H1-histamine receptor antagonists or H2-histamine receptor antagonists were applied, implying the role of H2-histamine receptor overexpression in sepsis (Brackett et al., 1985). Giving an inhibitor of histamine methyltransferase activity (an enzyme that degrades and, thus, inactivates histamine) enhanced the concentrations of histamine in the livers of LPS-treated mice, and this was accompanied by reduced mortality of the animals, conceivably because of a fall in tumor necrosis factor α levels (Yokoyama et al., 2007). In rabbits, after the induction of sepsis, the plasma histamine level increased 100-fold, whereas catecholamines in plasma of the same animals increased more slowly and to a lesser extent (to 130%; Matsuda et al., 2002). This was accompanied by an increase in heart rate and a fall in systolic and diastolic blood pressure. An H2-histamine receptor antagonist could attenuate this increase in heart rate (Matsuda et al., 2002). Interestingly, LPS increased the expression (mRNA and protein) of H1- and H2-histamine receptors in a rabbit ventricle, as well as the protein levels of the histidine decarboxylase (HDC), the pace-making enzyme for the in vivo synthesis of histamine (Matsuda et al., 2002). In H2-histamine receptor knockout mice or HDC knockout mice, LPS greatly reduced life expectancy (Yokoyama et al., 2004).

Because of H2-histamine receptors and their stimulation via histamine, cardiac tissue can apparently be protected in sepsis under isometric conditions. Fittingly, injection of histamine improved the prognosis (probably by the expression of tumor necrosis factor α) in HDC knockout mice (Yokoyama et al., 2004). On the other hand, LPS injection increased the HDC expression (as tested by Western blot and enzyme activity) in the liver and the amount of histamine and N-methylhistamine (indicative of a de novo production of histamine; Yokoyama et al., 2004). Histologically, in the liver, an induction of HDC was lacking in mast cells (likewise, the number of mast cells was not increased) but not in Kupffer cells (Yokoyama et al., 2004). However, our data show partial support of a similar way as Yokoyama et al.: H2-TG mice were functionally more compromised than WT mice after LPS treatment. We do not know whether this would be accompanied by increased mortality because such studies were not part of our permission from the ethical committee of our institution. We would predict that the mortality in our model would decline when pretreating the animals with H2-histamine receptor antagonists.

Emanating from ischemic hearts, plasma histamine levels can increase in many laboratory animals [as discussed in Genovese et al. (1988)]. Similar results have been obtained in hypoxia in human hearts [review: Reid et al. (2011)]. In the past, it has been speculated that this released histamine might originate from mast cells or from sympathetic nerve endings [as discussed in He et al. (2012)]. However, when doing these experiments in mast cell–deficient mouse hearts, one can still measure similar levels of histamine in ischemia (10 minutes in Langendorff System) in the eluate (He et al., 2012). This strongly argues against the role of mast cells in this phenomenon (He et al., 2012). In ischemic human cardiac tissue, histamine can be released (Hatta et al., 1997). Similar results have been reported in vivo in an animal system; for example, when the left descending coronary artery (LAD) was closed in dogs, and then in the coronary sinus, during LAD occlusion, the histamine levels in the plasma increased (about 10-fold to 1, 2 ng/ml), reaching a peak after 10 minutes and then declining to preocclusion values (although the occlusion of the LAD persisted) (Wolff and Levi, 1988). In our studies, there were different results that depended on the region of the heart used and the method to lower partial oxygen pressure in the heart.

For atrial preparations, we observed an inotropic benefit from H2-histamine receptor overexpression under basal conditions and preconditions, and these beneficial effects were cimetidine-sensitive; hence, in all likelihood, they were mediated by H2-histamine receptors on cardiomyocytes. For whole perfused hearts, a detrimental effect of H2-histamine receptor overexpression was apparent. It may be clinically relevant that under these conditions, reperfusion arrhythmias persisted longer: the existence of these arrhythmias can be explained by the elevation of intracellular cytosolic calcium ions because of histamine addition in isolated cardiomyocytes from H2-TG. It could be argued that our ischemic/hypoxic conditions were not severe enough to notice more pronounced differences; for instance, we could have used longer time periods of hypoxia and/or ischemia to cause substantial cell death and, thus, mimic cardiac infarction. However, this type of research was beyond the scope of the present work and might be subject to future reports.

Generally, severe sepsis and myocardial infarction (but also allergic processes) might lead to high levels of histamine. Usually, the heart, like other organs, tries to protect itself against continuous stimulation. The textbook example lies in cardiac protection against high amount of circulating β-adrenergic catecholamines in heart failure. A similar mechanism(s) might be active in the heart against histamine levels in the plasma. In vitro, the desensitization of the H2-histamine receptor has been carefully studied in cell cultures: functional homologous H2-histamine receptor desensitization has been found to be independent of a reduction of the number of H2-histamine receptors (Arima et al., 1993; Fernández et al., 2011). Desensitization has been found to be dependent not only on the time of exposure but also on the concentration of the agonist (Schreurs et al., 1984; Emami und Gespach, 1986). This is in line with our present findings. Ginsburg et al. (1980) mentioned (data not shown) that in isolated human cardiac electrically driven preparations, the response curves of repeated concentrations to histamine led to a rightward shift of the curves over time, which is consistent with desensitization; this is consistent with the present report. To the best of our knowledge, our study is the first to report actual data on H2-histamine receptor desensitization of cardiac tissue in vitro or in vivo. One could ask why we used histamine and dimaprit. Dimaprit was developed as a specific H2-histamine receptor agonist, whereas histamine has long been known to act agonistically on all four known H2-histamine receptors [as discussed in Gergs et al. (2019)]. Hence, we used dimaprit to stimulate more specific H2-histamine receptors than would be possible using histamine itself.

Hitherto, in register studies of patients, famotidine (a newer H2-histamine receptor antagonist that is chemically similar to cimetidine) reduced the incidence of heart failure or cardiac remodeling (Kim et al., 2004, 2006). Consistent with the role of histamine in human heart failure, higher concentrations of histamine have been reported in the blood of patients with idiopathic dilated cardiomyopathy (Zdravkovic et al., 2011). Thus, histamine has been suggested as contributing to heart failure, for instance, by augmenting fibrosis in heart failure patients (Patella et al., 1998). A 10-year-long observational study of humans initially free from any heart disease provided evidence for a reduced development of left or right ventricular cardiac hypertrophy in the study participants who took H2-histamine receptor antagonists (Leary et al., 2016, 2014).

In summary, our studies suggest that, in the heart, beneficial (in atrial hypoxia) and detrimental (e.g., in sepsis, reperfusion arrhythmias) effects of cardiac H2-histamine receptor expression occur. It is interesting to speculate that the same dichotomous role of H2-histamine receptors might also exist in humans, which needs to be studied further to decide which patients might benefit from H2-histamine receptor agonists or antagonists. In future studies, we will try to get better insights into the underlying pathways and pathomechanisms by extending biochemical analyses such as Western blotting and realtime quantitative PCR of already available and new tissue samples. In this context, histamine concentrations in the blood and in the cardiac tissue of our experimental animals will be analyzed to complete the data on the role of histamine in heart failure.

Authorship Contributions

Participated in research design: Gergs, Neumann.

Performed experiments and analyzed data: Kirchhefer, Bergmann, Künstler, Mißlinger, Au, Mahnkopf, Wache.

Wrote or contributed to the writing of the manuscript: Gergs, Neumann.

Footnotes

Abbreviations

DT
double transgenic
HDC
histidine decarboxylase
H1
histamine receptor type 1
H2
histamine receptor type 2
LAD
left descending coronary artery
LPS
lipopolysaccharide
PLB
phospholamban
PP2A
protein phosphatase 2A
TG
transgenic
WT
wild-type

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Research ArticleCardiovascular

H2 Receptor Expression and Cardiac Stress

Ulrich Gergs, Uwe Kirchhefer, Fabian Bergmann, Bernhard Künstler, Natascha Mißlinger, Bastian Au, Mareen Mahnkopf, Hartmut Wache and Joachim Neumann
Journal of Pharmacology and Experimental Therapeutics September 1, 2020, 374 (3) 479-488; DOI: https://doi.org/10.1124/jpet.120.000063
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