Published online before print September 15, 2003, doi: 10.1161/01.CIR.0000087595.17277.73
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(Circulation. 2003;108:1633.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Enhanced Gi Signaling Selectively Negates ß2-Adrenergic Receptor (AR)– but Not ß1-AR–Mediated Positive Inotropic Effect in Myocytes From Failing Rat Hearts
From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Md (R.X., S.Z., K.C., P.A., W.Z., E.G.L., H.C.); the Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Tex (R.A.B.); and the Departments of Physiology and Medicine, University of Maryland at Baltimore, and Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Md (C.W.B.).
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail xiaor{at}grc.nia.nih.gov
Received January 15, 2003; revision received May 20, 2003; accepted May 21, 2003.
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Abstract |
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Background— Myocardial contractile response to ß1- and ß2-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which Gi signaling and the ratio of ß2/ß1 are often increased. Because ß2-AR but not ß1-AR couples to Gs and Gi with the Gi coupling negating the Gs-mediated contractile response, we determined whether the heart failure–associated augmentation of Gi signaling contributes differentially to the defects of these ß-AR subtypes and, if so, whether inhibition of Gi or selective activation of ß2-AR/Gs by ligands restores ß2-AR contractile response in the failing heart.
Methods and Results— Cardiomyocytes were isolated from 18- to 24-month-old failing spontaneously hypertensive (SHR) or age-matched Wistar-Kyoto (WKY) rat hearts. In SHR cardiomyocytes, either ß-AR subtype–mediated inotropic effect was markedly diminished, whereas Gi proteins and the ß2/ß1 ratio were increased. Disruption of Gi signaling by pertussis toxin (PTX) enabled ß2- but not ß1-AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of ß2-AR ligands revealed that the contractile response mediated by most ß2-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent Gs and Gi activation. In contrast, fenoterol, another ß2-AR agonist, induced a full positive inotropic effect in SHR myocytes even in the absence of PTX.
Conclusions— We conclude that enhanced Gi signaling is selectively involved in the dysfunction of ß2- but not ß1-AR in failing SHR hearts and that disruption of Gi signaling by PTX or selective activation of ß2-AR/Gs signaling by fenoterol restores the blunted ß2-AR contractile response in the failing heart.
Key Words: receptors, adrenergic, beta • heart failure • proteins • contractility
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Introduction |
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Stimulation of ß-adrenergic receptors (ß-ARs) by catecholamines plays a pivotal role in regulating cardiac function. At least 2 ß-AR subtypes, ß1-AR and ß2-AR, are expressed in cardiac myocytes. Chronic heart failure in animal models and in humans is characterized by a severely diminished contractile response to both ß-AR subtypes.1–3 The heart failure–associated defect of ß-AR contractile response is accompanied by a selective downregulation of ß1-AR (resulting in a higher ß2/ß1 ratio1–3) and an increase in the amount or activity of pertussis toxin (PTX)–sensitive inhibitory G proteins (Gi) without any abnormality in stimulatory G proteins (Gs).3–5
Although ß1-AR and ß2-AR are closely related G protein–coupled receptors, these ß-AR subtypes couple to different G proteins6–9 and exhibit different effects on phosphorylation of protein kinase A (PKA) target proteins,10–13 cardiac excitation-contraction coupling,14,15 and cardiac cell survival and cell death.16–19 Most importantly, ß1-AR stimulation activates the Gs-cAMP-PKA signaling cascade, whereas the cardiac ß2-AR couples to PTX-sensitive Gi proteins, Gi2 and Gi3, in addition to Gs.6–9,16–19 The coupling of ß2-AR to Gi protein functionally confines the ß2-AR–Gs–stimulated cAMP/PKA signaling to a subsarcolemmal microdomain via the Gi-Gß
–phosphatidylinositol 3-kinase pathway10–15,20–22 and negates the Gs-mediated protein phosphorylation and positive inotropic effect in ventricular myocytes of many mammalian species (for review, see Reference 22).
The overall goal of the present study was to determine whether Gi signaling is selectively involved in the heart failure–associated defective contractile response to ß2-AR stimulation and, if so, to determine whether ß2-AR/Gs selective activation by certain agonists is able to restore the contractile support by ß-AR stimulation in the failing heart. Specifically, we (1) determined the abundance and function of both ß-AR subtypes (ß1-AR and ß2-AR) and G proteins (Gs and Gi) in cardiomyocytes from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY), (2) investigated the potential role of Gi signaling in the defects of ß-AR subtype–mediated contractile response in failing SHR cardiomyocytes, (3) and screened a number of ß2-AR ligands to identify "ß2-AR/Gs-signaling–selective" agonists and tested the agonists in cardiomyocytes from failing SHR hearts.
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Methods |
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Echocardiography and Hemodynamic Studies
Transthoracic echocardiographic studies were performed in rats as previously described.23 Briefly, a 2D short-axis view of the left ventricle (LV) was obtained at the level of the papillary muscles. M-mode tracings were recorded through the anterior and posterior LV walls. The percentage shortening of the endocardium was calculated as (LVDD-LVSD)/LVDDx100, where LVDD is LV internal diastolic dimension and LVDS is LV internal systolic dimension. The heart rates, blood pressures, and respiratory rates of all animals were monitored at monthly intervals. Blood pressure was measured by the tail-cuff method.
Measurement of Cardiac Myocyte Contraction
Myocytes were isolated from 18- to 24-month-old SHR or WKY rats by use of standard enzymatic techniques.14 Cells were perfused with a HEPES buffer containing (in mmol/L): 137 NaCl, 5.4 KCl, 1.2 MgCl2, 1 NaH2PO4, 1 CaCl2, 20 glucose and 20 HEPES (pH 7.4) and electrically stimulated at 0.5 Hz at 23°C. Cell length was monitored by an optical edge-tracking method as previously described.14 In a subset of experiments, aliquots of cells were incubated with PTX (1.5 µg/mL at 37°C for 3 hours).6 An individual myocyte was exposed to only 1 dose of 1 agonist, and measurements were obtained under steady-state conditions after a 10-minute exposure to the designated agonist.
Receptor Radioligand Binding
ß-AR radioligand binding studies were performed in membranes from LVs by use of the nonselective ß-AR antagonist [125I]-labeled cyanopindolol (125I-CYP), as described previously.15 Maximal binding (Bmax) was measured by use of a saturating amount of 125I-CYP on 25 µg of membrane protein from LVs. Inclusion of 10 µmol/L propranolol defined nonspecific binding. For competition isotherms, membranes (25 µg total protein) were incubated with 50 pmol/L 125I-CYP and increasing dilutions of ICI118,551 (ICI), a selective ß2-AR antagonist, as described previously.15 The percentage of ß2-AR was calculated by use of GraphPad Prism.
Western Analysis of Gs and Gi Proteins
Cardiac membranes from myocytes were used to determine Gs and Gi protein amounts by Western analysis.18 The antibodies recognizing the 
-subunits of Gi2, Gi3, and Gs were obtained from Santa Cruz Biotechnology.
Statistical Analysis
Results are expressed as mean±SEM. Significance was determined by use of Student’s t test, with a value of P<0.05 considered to be statistically significant.
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Results |
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Chronic Heart Failure Model: SHR
SHRs develop hypertension at
6 to 8 weeks of age. By the age of 18 to 24 months, 50% of these rats develop severe dilated chronic heart failure, many aspects of which have been characterized.24 At the time of study (ie, 18 to 24 months old), all SHRs used in this study had severe physical signs of heart failure (eg, resting tachycardia, tachypnea, pleural and/or pericardial effusions, and ascites). Cardiac dilation in the SHR group was evidenced by echocardiographic measurements (Table 1). Cardiac hypertrophy was confirmed by significant increases in the heart weight/body weight ratio, by echocardiographic measurements of LV posterior wall thickness, and by increased resting cell length (Table 1).
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Alterations in ß-AR Density and G Protein Abundance in Failing SHR Hearts
We first examined total ß-AR density, ß1- and ß2-AR subpopulations, and the abundance of Gs and Gi proteins in myocytes from 18- to 24-month-old SHR and age-matched WKY cardiac myocytes. There was a significant decrease (24%) in the Bmax in SHR relative to WKY hearts, without alterations in the binding affinity (Table 2). To define the relative abundance of ß1-AR and ß2-AR, competition isotherms were performed by use of the selective ß2-AR antagonist ICI. The ß2/ß1-AR ratio in control animals is 44/56, which is similar to the ratio previously reported.15 The ß2/ß1-AR ratio was significantly increased in SHR relative to WKY hearts (Table 2). This result indicates that the reduction in total ß-AR density is largely accounted for by the loss of ß1-AR. Thus, a selective downregulation of ß1-AR leads to a relative increase in the ß2-AR density in the failing SHR heart, a situation similar to what has been reported in failing human heart.1–3
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In addition, both Gi2 and Gi3 but not Gs were elevated by 2-fold in SHR compared with WKY hearts (Figure 1), resulting in an increase in the Gi/Gs ratio, as is the case in human heart failure.3–5 Taken together, these results suggest that the SHR heart failure model resembles human heart failure with respect to the major changes that occur in the proximal ß-AR signaling system.
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Disruption of Gi Signaling by PTX Selectively Restores ß2-AR– but Not ß1-AR–Mediated Positive Inotropic Effect in Cardiomyocytes From Failing SHR Hearts
Although the baseline contraction amplitude in myocytes from failing SHR hearts was not significantly different from that of control animals (see Figure 2 legend), the positive inotropic effect of either ß-AR subtype stimulation was markedly attenuated. Figure 2A shows that myocyte contractile response to ß1-AR stimulation by norepinephrine (NE) in the presence of 1-AR and ß2-AR blockade by prazosin (10-6 mol/L) and ICI (10-7 mol/L), respectively, was markedly blunted in SHR myocytes compared with that in WKY cells, consistent with the downregulation of the receptor density. Figure 2B illustrates that ß2-AR stimulation by zinterol had only a minor positive inotropic effect in SHR ventricular myocytes, whereas it enhanced the contraction amplitude by >2-fold in control cardiomyocytes from age-matched WKYs. The dose-response curve of zinterol to increase contraction amplitude was severely shifted downward in SHR compared with WKY. Thus, myocyte contractile response to either ß1-AR or ß2-AR was overtly attenuated in SHR cardiomyocytes relative to WKY myocytes, even though only ß1-AR density was selectively downregulated, with little change in ß2-AR density in SHR hearts (Table 2).
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To test the hypothesis that exaggerated Gi signaling might be differentially involved in the impairment of ß2-AR versus that of ß1-AR in the failing heart, we treated myocytes with PTX to disrupt Gi function. Remarkably, PTX not only enhanced the contractile response to ß2-AR stimulation in both failing SHR and control myocytes but also abolished the difference between the 2 groups (Figure 2B). In contrast, PTX did not affect the whole dose-response of ß1-AR stimulation by NE in either WKY or SHR myocytes (Figure 2A). These results indicate that enhanced Gi signaling is specifically involved in the defect of ß2-AR contractile response but not in the dysfunction of ß1-AR signaling in the SHR heart failure model. These results also suggest that ß2-AR–coupled Gs signaling remains largely intact in the failing heart.
Screening for Ligands Bypassing ß2-AR/Gi Pathway
To determine whether disruption or avoidance of the ß2-AR–coupled Gi signaling pathway is able to restore ß2-AR–mediated contractile support in the failing SHR heart, we searched for ligands that activate ß2-AR–coupled Gs signaling but not the Gi pathway. Six known ß2-AR–selective agonists and 2 nonselective ß-AR agonists were tested in the presence of the ß1-AR antagonist CGP20712A (CGP; 3x10-7 mol/L). Zinterol had been well characterized in previous studies as a selective ß2-AR agonist.6–9,10–15 The specificity of other tested agonists, including salbutamol, procaterol, and fenoterol, for ß2-AR stimulation was verified by the fact that the highly selective ß1-AR antagonist CGP (3x10-7 mol/L) did not block their contractile responses, whereas it fully abolished the effect induced by the ß1-AR agonist NE (10-7 mol/L) (Figure 3). Cell contractile response to ß-AR stimulation and its PTX sensitivity were then measured to represent the overall readout of Gs (in PTX-treated cells) or combined Gs-Gi signaling (in non–PTX-treated cells).
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Most ligands tested, including salbutamol, procaterol, and zinterol, enhanced the contraction amplitude of WKY myocytes in a dose-dependent manner, with a maximal increase of 2-fold (Figure 4A through 4C). Inhibition of Gi function by PTX enabled the ß2-AR agonists to induce a full contractile response, with the maximal response being a 3-fold increase (Figure 4A through 4C). In other words, with respect to their inotropic effects, inhibition of Gi signaling converted these partial ß2-AR agonists to full agonists. These results are consistent with previous findings that ß2-AR can simultaneously activate Gs and Gi.6–9 A similar potentiating effect of PTX was observed for ß2-AR stimulation induced by other known ß2-AR agonists such as terbutaline and celenbuterol, or by nonselective agonists, epinephrine and isoproterenol, plus the ß1-AR blocker CGP (data not shown).
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Interestingly, another selective ß2-AR agonist, fenoterol,25 evoked a full contractile response that was insensitive to PTX treatment (Figure 4D). It appears that fenoterol selectively stimulates the ß2-AR/Gs signaling pathway, whereas other ß2-AR agonists activate both Gs and Gi proteins in terms of their effects on cardiac myocyte contractility.
Rescue of the Depressed ß2-AR Contractile Response by Fenoterol in Myocytes From Failing SHR Hearts
We next determined whether the apparent ß2-AR/Gs signaling–specific agonist fenoterol could rescue the diminished contractile response to ß2-AR stimulation in myocytes from failing SHR hearts. Figure 5A shows typical continuous recordings of myocyte contractile responses to zinterol or fenoterol. Fenoterol induced a robust increase in contraction amplitude in a representative SHR cell. This effect was completely reversed by the ß2-AR antagonist ICI (10-7 mol/L), indicating that the positive inotropic effect of fenoterol is mediated by selective ß2-AR stimulation. In contrast, zinterol had a very minor effect in another cell from the same heart. Figure 5B shows the average dose-response of contraction amplitude to fenoterol in cardiomyocytes from SHR and age-matched WKY rats. The 2 dose-response curves virtually overlapped each other, in sharp contrast to the markedly suppressed contractile response to zinterol in failing SHR heart cells (Figure 2B). Thus, fenoterol is able to restore a full contractile response to ß2-AR stimulation in SHR myocytes even in the absence of PTX, thereby abolishing the difference between SHR and WKY.
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Discussion |
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Enhanced Gi Signaling Selectively Contributes to the Diminution of ß2-AR– but Not ß1-AR–Mediated Contractile Response in Myocytes From Failing SHR Hearts
Although previous studies have demonstrated that PTX treatment partially restores the diminished contractile response to mixed ß-AR stimulation in a rat myocardial infarction heart failure model26 and in myocytes from failing human hearts,27 the present study provides the first documentation that enhanced Gi signaling is, in fact, selectively involved in heart failure–associated attenuation in ß2-AR– but not ß1-AR–mediated increase in myocyte contractility. This is because inhibition of ß2-AR/Gi signaling by PTX treatment enables ß2-AR stimulation to induce a full contractile response, thus abolishing the difference between the failing and normal hearts, whereas it does affect ß1-AR–induced inotropic effect. These findings are consistent with our previous notion that ß2-AR but not ß1-AR dually couples to Gs and Gi and that the Gi coupling exhibits an inhibitory effect on the Gs signaling.6–9
Although the heart failure–associated defect of ß2-AR contractile response is largely attributable to enhanced ß2-AR/Gi signaling, multiple mechanisms might be involved in ß1-AR dysfunction, including receptor downregulation1–3 (Table 2) and receptor desensitization resulting from upregulated G protein–coupled receptor kinases. In this regard, it has been shown that the level and enzymatic activity of ß-AR kinase 1 (ßARK1), a prototypic G protein–coupled receptor kinase,28 are significantly elevated in human29 and SHR failing hearts.30 The increased ßARK1 abundance/activity may contribute to the reduced ß1-AR signaling in chronically failing hearts. Further studies are needed to determine the relative contributions of enhanced Gi function and ßARK1 to subtype-specific defects of ß-AR in the context of heart failure.
Selective Downregulation of ß1-AR May Serve as a Protective Mechanism in Heart Failure
It has been highly controversial as to whether enhancing ß-AR signaling is beneficial or deleterious for the failing heart. The prevalent view is that chronically increasing nonselective ß-AR stimulation is toxic to the heart, because there is an inverse relationship between the plasma level of catecholamines and survival in heart failure patients31 and because ß-AR blockade reduces both the morbidity and mortality in heart failure patients.32 More recent studies have demonstrated that ß1-AR induces apoptosis in cultured rodent cardiomyocytes.16–19 Similarly, cardiac transgenic overexpression of ß1-AR in mice leads to marked myocyte hypertrophy, apoptosis, and heart failure.33,34 Thus, chronic ß1-AR stimulation is detrimental to the myocardium.
In contrast, selective enhancement of ß2-AR signaling might be beneficial for the failing heart. This hypothesis is supported by the fact that ß2-AR stimulation protects cardiac myocytes against a wide array of apoptotic insults.16–19 In addition, overexpression of cardiac ß2-AR by 100- to 200-fold does not induce hypertrophy or heart failure,35 at least up to the age of 1 year. In fact, crossing transgenic mice overexpressing cardiac ß2-AR at appropriate levels (30-fold) with transgenic mice overexpressing Gq not only improves cardiac performance but also prevents hypertrophy in the Gq overexpression heart failure model,36 although extremely high levels of ß2-AR overexpression induce pathological phenotypes36,37 and fail to rescue the genetic mouse heart failure model.36,37 Furthermore, the beneficial effect of ß2-AR stimulation in the context of heart failure is clearly supported by the analysis of polymorphisms of ß2-AR in chronic heart failure patients. The prognosis of heart failure patients with Ile164 polymorphism (a Thr-to-Ile switch at amino acid 164 with reduced ß2-AR signaling)38 relative to patients without the ß2-AR variant is much worse, and they are significantly more likely to receive earlier aggressive interventions or cardiac transplantation.39
In the present study, we found that in failing SHR hearts, ß1-AR is selectively downregulated with little or no loss of ß2-AR, similar to the situation of chronic human heart failure.1–3 In light of evidence for the opposing effects of ß1-AR and ß2-AR stimulation on cardiac myocyte apoptosis16–19 and the distinct phenotypes of transgenic overexpression of ß1-AR versus ß2-AR,33–35 the selective downregulation of ß1-AR may represent a cardiac protective mechanism to slow the progression of cardiomyopathy and contractile dysfunction.
Selective Activation of ß2-AR/Gs Signaling in Failing SHR Hearts
Because heart failure in many instances is related to a selective loss of ß1-AR and because chronic stimulation of ß2-AR exhibits no known detrimental effects, as discussed above,35 ß2-AR would appear to be a potentially important therapeutic target for the treatment of chronic heart failure. However, most of the commonly used nonselective ß-AR agonists (eg, isoproterenol) cannot discriminate ß2-AR from ß1-AR. In addition, most ß2-AR agonists cannot discriminate ß2-AR–coupled Gs signaling from Gi signaling. The situation is even worse in chronically failing hearts with elevated Gi signaling, such that ß2-AR stimulation by zinterol elicits only a minor contractile response (Figure 2). To unmask the ß2-AR/Gs signaling from the inhibition by Gi, we identified fenoterol as an apparent ß2-AR/Gs–selective agonist, as evidenced by the lack of PTX sensitivity of its positive inotropic effect (Figure 3). In cardiomyocytes from failing SHR hearts, fenoterol elicits a contractile response that is comparable to that in cells from nonfailing WKY heart cells (Figure 4). It is also noteworthy that there may be some advantages to use of fenoterol instead of ß1-AR agonists to provide contractile support in the failing heart. Our preliminary experiments have shown that, unlike ß1-AR stimulation, ß2-AR stimulation by fenoterol does not induce cardiac myocyte apoptosis (Zhu et al, unpublished data), although it increases cAMP/PKA signaling, perhaps because of distinct compartmentation of cAMP signal in response to different ß-AR subtype activation.11–13,40,41
Regarding receptor theory, the Gs-specific ß2-AR stimulation, as demonstrated here for native ß2-AR in intact cardiomyocytes, provides new evidence to support the idea that there are multiple active conformational states for a given receptor42–45 and that ligands may lead the receptor to a subset of downstream signaling pathways (ligand-directed receptor trafficking).45 In contrast to fenoterol, a well-characterized ß2-AR inverse agonist, ICI, can direct ß2-AR to a Gi-coupled form and result in a negative inotropic effect in cardiomyocytes from failing human hearts or rabbit and mouse myocytes in which ß2-AR and/or Gi proteins are overexpressed.44
In summary, the present study reveals 3 major findings. First, enhanced Gi signaling is selectively involved in the dysfunction of ß2-AR but not of ß1-AR. Inhibition of Gi signaling with PTX enables ß2-AR stimulation to induce a full contractile response in myocytes from failing SHR hearts without affecting ß1-AR contractile response. Second, ß2-AR–coupled Gs and Gi pathways appear to be activated in an agonist-dependent manner. Most agonists tested stimulate both pathways, whereas fenoterol predominantly activates Gs signaling, as manifested by the lack of PTX sensitivity of its positive inotropic effect. Third, the apparent ß2-AR/Gs–selective agonist fenoterol fully restores ß2-AR contractile response in failing SHR hearts. Therefore, we conclude that enhanced Gi signaling is specifically involved in the dysfunction of ß2-AR but not of ß1-AR in regulating myocyte contractility in the failing heart and that an apparent selective activation of ß2-AR–coupled Gs, bypassing the Gi pathway, provides a novel means to restore the diminished ß2-AR responsiveness in the SHR heart failure model. Thus, signaling-selective receptor stimulation by agonists may offer a wide range of novel therapeutic opportunities by enhancing the desired effects while avoiding the adverse side effects of therapeutic agents.
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Acknowledgments |
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This work was supported by the National Institutes of Health (NIH) intramural research programs (Drs Xiao, Lakatta, and Cheng), NIH extramural grants (Drs Bond and Balke), and the American Heart Association (Dr Balke).
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Footnotes |
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All authors except Drs Balke and Bond are employees of the US Government.
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References |
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