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CARDIOVASCULAR
Departments of Pharmaco-Biology (T.A., M.C.C.) and Cell Biology (T.A., M.C.C., B.T.), University of Calabria, Arcavacata di Rende, Italy; and Institut National de la Santé et de la Recherche Médicale U575 Physiopatologie du Système Nerveux, Strasbourg, France (Y.G., M.-H.M.-B., D.A., T.A.)
Received January 31, 2006; accepted April 6, 2006.
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Abstract |
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; Ojika et al., 2000). In cholinergic neurons, HCNP exerts dose-dependent and time-dependent increases of both activity and Vmax of choline acetyltransferase (Ojika et al., 1994), inducing the key enzyme expression required for ACh synthesis and influencing the development of cholinergic phenotypes (Ojika et al., 1994). HCNP is the endogenous N-terminal fragment of the precursor protein phosphatidylethanolamine-binding protein (PEBP), alternatively named Raf-1 kinase inhibitor protein since it interacts with cytoplasmic Raf1 (Yeung et al., 1999). PEBP is ubiquitous, as documented by its occurrence in a wide range of organisms such as bacteria, yeasts, plants, nematodes, Drosophila, and mammals (Schoentgen and Jolles, 1995). It has been shown, particularly in mammals, that members of the PEBP family are involved in several signaling systems, modulate the action of heterotrimeric G-proteins, and inhibit several serine proteases (Hengst et al., 2001) as well as mitogen-activated protein kinase and nuclear factor-
B pathways (Vallèe et al., 2003). Studies on the relationships between structural and physicochemical features of HCNP and its precursor highlight an important dual function of this undecapeptide (Vallèe et al., 2003). First, HCNP is the N-terminal positively charged region of PEBP; therefore, it is able to interact with negatively charged membranes by competition between intramolecular and intermolecular electrostatic interactions (Vallèe et al., 2003). At the same time, it participates in conformation and stability of the active site of PEBP by hydrogen-bonding ability. Second, after its specific cleavage, free in solution, HCNP appears well structured, at least in its central region (peptide sequence: D3LSKW7), whose conformation is similar to that observed in crystallized PEBP (Vallèe et al., 2003). Therefore, free HCNP is suited to act as a signal in target cells and tissues, thereby contributing to some of the biological functions of PEBP (Hengst et al., 2001; Vallèe et al., 2003; Keller et al., 2004).
Beyond their presence in the nervous tissue, both PEBP (e.g., adult rat; Frayne et al., 1999) and HCNP (e.g., young rat; Katada et al., 1996) have been immunolocalized in other organs and tissues, including blood vessel walls, adrenal gland, intestine, and kidney. In addition, PEPB expression has been detected on Western blots of heart and liver extracts (Frayne et al., 1999). Recently, an estimation of PEBP concentration in bovine serum, obtained after protein sequencing, indicated a value of 35 nM (Goumon et al., 2004). More recently, using chromaffin cells from bovine adrenal medulla as a well characterized secretion model, we demonstrated that PEBP and HCNP are present in chromaffin cells (intragranular matrix), from which they are secreted into the circulation with catecholamines (Goumon et al., 2004). In addition, PEBP and HCNP have been detected with lipid rafts, in platelet secretion and in serum (Goumon et al., 2004), in the cerebrospinal fluid of Alzheimer patients (Tsugu et al., 1998), and in murine adipocytes (Kratchmarova et al., 2002). PEBP was shown to be involved with several signaling cascades, interfering with mitogen-activated protein kinase kinase phosphorylation and activation by Raf-1 (Yeung et al., 1999). Moreover, it was also postulated that PEBP is involved in growth, transformation, and differentiation, which are often deregulated in many forms of cancer (Keller et al., 2004). Identified in the testis and epididymis, PEBP has been implicated in spermatogenesis (Perry et al., 1994). These data, together with its multiple organ localization, suggest that PEBP is a multifunctional protein with roles in reproduction, cardiology, and neurology.
To have an insight of the functional features of HCNP as a signaling peptide, we have recently used an in vitro frog working heart preparation as a bioassay system demonstrating that HCNP from 10-11 to 10-7 M depresses the contractile performance, i.e., it exerts a negative inotropic action, counteracting, at the same time, the classic positive inotropic effect of 
-adrenergic agonists [i.e., isoproterenol (ISO)] (Goumon et al., 2004).
In the present article, using the rat isolated and Langendorff perfused heart, a well known paradigm of cardiac physiology, we have provided evidence that rat HCNP counteracts the excitatory positive inotropy of ISO. We have also shown that HCNP interacts with the cardiac ACh signal transduction pathway, thus corroborating the idea that this undecapeptide may play a novel role as an inhibitory cardiac modulator.
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Materials and Methods |
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Isolated Heart Preparation
Rats were anesthetized with i.p. injection of ethyl carbamate (2 g/kg body weight). The hearts were rapidly excised and transferred in ice-cold buffered Krebs-Henseleit solution (KHs). The aorta was immediately cannulated with a glass cannula and connected with the Langendorff apparatus to start perfusion at a constant flow rate of 12 ml/min (Cerra et al., 2005). Fluid accumulation was prevented by piercing the apex of the left ventricle. A water-filled latex balloon, connected to a BLPR gauge (Wolfram Research, Inc., Champaign, IL), was inserted through the mitral valve into the left ventricle to allow isovolumic contractions and continuous recording of mechanical parameters. The balloon was progressively filled with water up to 80 µl to obtain an initial left ventricular end diastolic pressure of 5 to 8 mm Hg. Coronary pressure was recorded using another pressure transducer located just above the aorta. The perfusion solution consisted of a modified nonrecirculating KHs containing 113 mM NaCl, 4.7 mM KCl, 25 mM NaHCO3, 1.2 mM MgSO4, 1.8 mM CaCl2, 1.2 mM KH2PO4, 11 mM glucose, 1.1 mM mannitol, and 5 mM Napyruvate. pH was adjusted to 7.4 with NaOH, and the solution was equilibrated at 37°C with 95% O2-5% CO2. All drug-containing solutions were freshly prepared before the experiments. ISO hydrochloride, carbachol, atropine, pirenzepine, and pertussis toxin (PTx) were purchased from Sigma Chemical Co. (St. Louis, MO). 11-((2-Diethylamino)methyl)-1-piperidinyl)acetyl)-5,11-dihydro-6H-pyrido-(2,3-b)(1-4) benzodiazepine-6-one (AFDX116) was a generous gift from Boehringer Ingelheim (Biberach, Germany). Rat HCNP (rH-CNP) was synthesized at the Institut National de la Santé et de la Recherche Médicale U575 Physiopathology of Nervous System (Strasbourg, France).
For peptide synthesis, acetylated rat HCNP was synthesized on an Applied Biosystems 433A peptide synthesizer (Applied Biosystems, Foster City, CA), using the step-wise solid-phase synthetic approach with 9-fluorenylmethoxycarbonyl. A sodium-acetyl-alanine residue was used to obtain the acetylated peptide. The peptide was further purified by reverse-phase high-performance liquid chromatography on a preparative Macherey-Nagel column, Nucleosil RP 300-7C18 (10 x 250 mm). The peptide purity was checked by protein sequencing on an Applied Biosystems 473A protein sequencer and matrix-assisted laser desorption ionization/time of flight mass spectrometry analysis (Biflex II; Bruker, Newark, DE), showing a purity of >95%. Hemodynamic parameters were assessed using a PowerLab data acquisition system and analyzed using Chart software (ADInstruments, Basile, Italy).
Experimental Protocols
Basal Conditions. Rat isolated and Langendorff perfused heart performance was evaluated by analyzing heart rate (HR; in beats per minute), left ventricular pressure (LVP; in millimeters of mercury), rate pressure product (RPP; HR x LVP, in 104 millimeters of mercury per beats per minute), and the maximal rate of left ventricular pressure contraction [+(LVdP/dt)max]. LVP and RPP were used as indexes of contractile activity and cardiac work (Georget et al., 2003), respectively. The mean coronary pressure (CP; in millimeters of mercury) was calculated by averaging the coronary pressure during several cardiac cycles.
Drug Application. HCNP-stimulated preparations. To test desensitization, we preliminarily perfused the heart with single repeated doses of HCNP at 10-10 and 10-7 M, revealing the absence of desensitization. In fact, each peptide dose produced a reduction of LVP of 16.6 ± 3.59 and 20.83 ± 5.09%, respectively. Thus, concentration-response curves were generated by perfusing the cardiac preparations with KHs including increasing concentrations of rH-CNP (from 10-14 to 10-6 M) for 10 min.
Cholinergic-stimulated preparations. To obtain preliminary information on the cholinergic action of rHCNP toward the carbachol-dependent stimulation, dose-response curves were produced by perfusing the cardiac preparations with KHs enriched with increasing concentrations of rHCNP (from 10-12 to 10-7 M) alone. These curves were then compared with those obtained by exposing other cardiac preparations with the same perfusion medium containing increasing concentrations of rHCNP (from 10-12 to 10-7 M) plus a single concentration of carbachol (10 nM) or a single concentration of atropine (1 µM) or a single concentration of AFDX116 (100 nM) or a single concentration of pirenzepine (1 nM). In all protocols, the hearts were perfused with KHs enriched with the specific drug before and after the addition of HCNP. The antagonist concentration was selected on the basis of the results of preliminary dose-response curves as the highest dose that did not significantly affect cardiac performance.
Gi/Go Protein Involvement
To verify the involvement of Gi/Go protein in the action mechanism of rHCNP, dose-response curves were produced by perfusing the hearts with KHs enriched with increasing concentrations of rHCNP (from 10-12 to 10-7 M) alone. These curves were then compared with those obtained by exposing other cardiac preparations with the same perfusion medium containing increasing concentrations of rHCNP (from 10-12 to 10-7 M) plus a single concentration of PTx (0.01 nM). As shown in the rat heart, PTx catalyzes the ADP ribosylation of the 
-subunit of Gi/Go and uncouples the interaction between Gi and inhibitory receptors of adenylate cyclase, such as muscarinic receptors (Cohen-Armon and Sokolowsky, 1991; Grimm et al., 1998). The hearts were preincubated with PTx for 60 min.
Isoproterenol-Stimulated Preparations
To evaluate whether rHCNP antagonizes the ISO stimulation, dose-response curves of ISO (from 10-10 to 10-6 M) alone were compared with those obtained by exposing other cardiac preparations to the same perfusion medium containing increasing concentrations of ISO (from 10-10 to 10-6 M) plus a single concentration of rHCNP (10-11 M).
Statistics
Data are expressed as the mean ± S.E.M. Since each heart represents its own control, the statistical significance of differences within group was assessed using paired Student's t test (p < 0.05). Comparison between groups was made by using a one-way analysis of variance (ANOVA) followed by Duncan's and Bonferroni's multiple comparison test. Differences were considered to be statistically significant for p < 0.05. The concentration-response curves of LVP reduction induced by rHCNP alone and by rHCNP plus carbachol or atropine or AFDX116 or pirenzepine were fitted using Prism 4.02 (GraphPad Software Inc., San Diego, CA). This provided, for each curve, the -log of the concentration (molar) that induced the EC50 of rHCNP alone and rHCNP plus carbachol, atropine, AFDX116, and pirenzepine. The same fitting procedure was used to calculate the EC50 of ISO alone and of ISO plus rHCNP on LVP and RPP.
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Cholinergic-Stimulated Preparations. To explore the interaction between rHCNP and intracardiac cholinergic signaling, hearts were perfused with KHs containing carbachol (10 nM), a nonselective cholinergic agonist resistant to the action of cholinesterases, in addition to increasing concentrations of rHCNP (from 10-12 to 10-7 M). Carbachol, at this concentration, did not modify LVP and RPP reductions induced by rHCNP. In the presence of carbachol, rHCNP did not affect HR, except for a small significant decrease observed at 10-10 and 10-9 M. At all concentrations, rHCNP plus carbachol induced a significant increase of CP (Fig. 3). Atropine (1 µM), a competitive nonselective antagonist of muscarinic receptors, abolished the LVP reduction induced by rHCNP at 10-12, 10-8, and 10-7 M, whereas it reduced these effects at 10-11,10-10, and 10-9 M. Atropine abolished or reduced the inhibitory effect of rHCNP on RPP, depending on lower or higher peptide concentrations, respectively. Muscarinic receptor blockade did not affect HR or CP (Fig. 4). The computerized fitting of the curves indicated the percentages of LVP variations obtained in the presence of rHCNP alone and rHCNP plus either carbachol (10 nM) or atropine (1 µM) (Fig. 5). The sigmoid concentration-response curves and EC50 values (Fig. 5) showed a noncompetitive antagonism of atropine on the rHCNP-mediated negative inotropism.
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To explore the involvement of different muscarinic receptor subtypes, rHCNP effects were evaluated in the presence of a single concentration (100 nM) of either AFDX116 or pirenzepine, competitive selective antagonists of M2- and M1-M3 subtype receptors, respectively. The treatment with AFDX116 abolished the LVP reduction induced by rHCNP at 10-12, 10-11, and 10-10 M, whereas significantly reducing it at 10-9, 10-8, and 10-7 M. AFDX116 abolished the inhibitory effect of rHCNP on RPP at low peptide concentrations, without affecting it at higher peptide concentrations. The treatment with the M2-receptors antagonist induced a HR reduction at high concentrations and a vasoconstriction from 10-10 to 10-7 M (Fig. 6). In contrast, blockade of M1-M3 receptors by pirenzepine was without significant effect on the rHCNP-induced cardiac effects (Fig. 7).
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-adrenergic-mediated positive chronotropism, inotropism, and coronary dilation, dose-response curves were generated by perfusing heart preparations with increasing concentrations of ISO (from 10-10 to 10-6 M) alone and together with a single concentration of rHCNP (0.01 nM). rHCNP abolished the ISO (from 5 x 10-9 to 10-7 M)-mediated positive increase of LVP and RPP. rH-CNP reduced HR at low ISO concentrations (up to 50 nM), whereas it increased HR at high ISO concentrations (0.5 and 1 µM). CP was not modified (Fig. 10). Figure 1C shows a representative trace of 0.01 nM HCNP effects in the presence of a single ISO concentration (5 nM).
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Discussion |
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).
Basal Conditions. Under basal conditions (i.e., nonstimulated), HCNP appears to act as an efficient negative modulator of myocardial performance since it depresses relevant contractile parameters, such as LVP and RPP, within a nanomolar range of concentrations. Significant effects were elicited by HCNP at the same concentrations of its precursor, PEPB, found in the bovine serum (Goumon et al., 2004). Notably, the concentration-response curves show that neither HR nor CP is modified by HCNP, highlighting a selective inotropic characteristic of the peptide. This feature makes it of particular interest for physiopharmacological studies designed to analyze myocardial contractility separately from rhythmogenic or coronary motility.
Cholinergic Signaling. The findings that HCNP-dependent negative inotropism is enhanced in the presence of cholinergic stimuli (i.e., carbachol) and is abolished in the presence of nonspecific muscarinic inhibition (i.e., atropine) demonstrate the undecapeptide involvement in the cardiac cholinergic signal transduction pathway. Moreover, using selective muscarinic subtype inhibitors, we provide evidence that HCNP acts as a functional agonist of ACh at the M2 subtype receptors level, without any significant interaction with the M1-M3 receptor subtypes. In the human heart, M2 subtype is preferentially located on the myocardiocytes (Fu et al., 1994). In the rat heart, M2 muscarinic receptors were detected mainly on the sarcolemma and T-tubules of the ventricular cardiomyocytes (Hove-Madsen et al., 1996). They are principally coupled to adenylate cyclase inhibition, reduce intracellular cAMP levels, and decrease the L-type Ca2+ current, thereby eliciting negative cholinergic chronotropic and inotropic effects (for references, see Hove-Madsen et al., 1996; Gattuso et al., 1999). However, it cannot be excluded that in other tissues, e.g., endothelial cells, HCNP may exert functional effects via interaction with M1-M3 receptors. A functional heterogeneity of cardiac muscarinic receptors has been reported in the human heart. It has been shown that they exert physiological effects considerably different between atrium and ventricle, these differences being attributed to coupling with different G-proteins and downstream cascades (Mittmann et al., 2003). It could be that HCNP interacts with ventricular muscarinic receptors differently from how it interacts with the receptors expressed in the conduction system. This may contribute to explain why HCNP did not exert chronotropic effects. The finding that, on the bases of EC50 values, AFDX116 exerts competitive inhibition on HCNP-mediated negative inotropism, whereas atropine appears to act in a noncompetitive manner, cannot be explained by the present study. In the absence of a demonstration of a direct interaction of HCNP with the receptor binding site, alternative explanations (e.g., allosteric modulation) should be taken into consideration. In the Langendorff heart preparation, the sympathetic postganglionic fibers are denervated because they are separated from the ganglion cell bodies in the stellate ganglia, whereas parasympathetic preganglionic fibers are transected decentralizing the heart. This allowed us to evaluate HCNP effects without parasympathetic and sympathetic extrinsic influences. However, since the rat ventricles exhibit a high cholinergic nerve density, an intracardiac release of ACh by the peripheral nerve endings cannot be excluded. Cholinergic-mediated negative inotropism can also be elicited by activation of constitutive nitric-oxide synthase activity linked to the muscarinic receptor-G-protein system detected in the caveolae of ventricular myocytes of several mammalian hearts (for references, see Dessy et al., 2000). Our results are consistent with an endothelium-independent inotropic action of HCNP, indicating that the peptide directly targets the myocardium. Remarkably, the HCNP-mediated inotropism is G-protein dependent. Using the precursor of HCNP, i.e., the human PEBP, it has been shown that human PEBP modulates G-protein and G-protein-coupled receptor signaling (Kroslak et al., 2001).
Receptor-receptor interactions between G-protein-coupled receptors occurring at the plasma membrane level have been identified. In particular, it has been shown that clustering of G-protein-coupled receptors in aggregates or receptor mosaics results in the reciprocal modulation of their binding and decoding characteristics, their cooperativity playing an important part in the decoding of signal transduction (Agnati et al., 2005).
The analysis of the interactions between HCNP and the adrenergic system has revealed that the peptide exerts a functional competitive antagonism. This was shown by the right shift of the sigmoid curves of LVP and RPP. HCNP modified ISO-dependent chronotropism with a biphasic effect. In fact, HCNP reduced the positive chronotropic effect of low ISO concentrations while it increased the ISO effect at higher concentrations. Presently, we cannot explain the mechanisms underlying the biphasic effect of HCNP on ISO-dependent positive chronotropism. Changes in the ratio of intracellular modulators (i.e., cAMP/cGMP), which may be related to this effect, can be postulated (Casadei and Sears, 2003 and refs. therein). Taken together, these data suggest that by mimicking ACh, HCNP in the rat heart may act as a new cholinergic modulator through direct interaction with the G-protein-muscarinic coupled receptor signal transduction system localized at the myocardiocyte sarcolemmal level. HCNP-induced activation of the cholinergic pathway appears to counteract functionally the adrenergic pathway, thereby modulating myocardial contractility under basal conditions and under adrenergic stimulations.
This putative role of HCNP and its precursor PEBP may provide a new breakthrough regarding the important functional link between the brain and the cardiovascular system, achieved through two pathways, i.e., the autonomic nervous system acting via direct neural actions and the neuroendocrine humoral outflow acting via the hypothalamic-pituitary-adrenal axis. Since the 1930s, Walter Cannon, studying the stress response, by him named as "fight or flight" reaction, recognized the "wisdom of the body" in the "generalized" sympathetic response acting during stress and emphasized, at the same time, the more "discrete" influences exerted by the parasympathetic nervous system (Chrousos and Gold, 1992). The heart, being an integrative interface between the noradrenergic nerve terminals, releasing noradrenaline, and the circulating catecholamines secreted by the adrenal medulla, represents a classic paradigm of a stress-threatened organ. Elevated catecholamine levels have long been known to induce necrotic heart damage, since the pioneer work of Raab (Raab, 1963; Teerlink et al., 1994; Tan et al., 2003; and refs. therein). Knowledge on HCNP and cardiac signaling may provide a new molecular dimension to the "wisdom of the body," uncovering how the sympathetic and parasympathetic systems influence effector tissues homeostasis and, at the same time, how overactivation of the adrenergic system during the onset and course of pathophysiological conditions may be functionally counteracted.
In conclusion, our present study strongly suggests that HCNP and the precursor protein PEBP are new endocrine factors involved in the control of cardiac function physiology in mammals.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: HCNP, hippocampal cholinergic neurostimulating peptide; ACh, acetylcholine; PEBP, phosphatidylethanolamine-binding protein; ISO, isoproterenol; KHs, Krebs-Henseleit solution; PTx, pertussis toxin; AFDX116, 11-((2-diethylamino)methyl)-1-piperidinyl)acetyl)-5,11-dihydro-6H-pyrido(2,3-b)(1-4) benzodiazepine-6-one; rHCNP, rat HCNP; HR, heart rate; LVP, left ventricular pressure; LVP, left ventricular pressure; RPP, rate pressure product; +(LVdP/dt)max, maximal rate of left ventricular pressure contraction; CP, coronary pressure; ANOVA, analysis of variance.
Address correspondence to: Dr. Bruno Tota, Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy. E-mail: tota{at}unical.it
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, p < 0.05.
