Catecholamines, Cardiac β-Adrenergic Receptors, and Heart Failure
2000; Lippincott Williams & Wilkins; Volume: 101; Issue: 14 Linguagem: Inglês
10.1161/01.cir.101.14.1634
ISSN1524-4539
AutoresRobert J. Lefkowitz, Howard A. Rockman, Walter J. Koch,
Tópico(s)Pharmacological Effects and Assays
ResumoHomeCirculationVol. 101, No. 14Catecholamines, Cardiac β-Adrenergic Receptors, and Heart Failure Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCatecholamines, Cardiac β-Adrenergic Receptors, and Heart Failure Robert J. Lefkowitz, Howard A. Rockman and Walter J. Koch Robert J. LefkowitzRobert J. Lefkowitz From the Howard Hughes Medical Institute and the Departments of Medicine and Biochemistry (R.J.L.), Department of Medicine (H.A.R.), and Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC. , Howard A. RockmanHoward A. Rockman From the Howard Hughes Medical Institute and the Departments of Medicine and Biochemistry (R.J.L.), Department of Medicine (H.A.R.), and Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC. and Walter J. KochWalter J. Koch From the Howard Hughes Medical Institute and the Departments of Medicine and Biochemistry (R.J.L.), Department of Medicine (H.A.R.), and Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC. Originally published11 Apr 2000https://doi.org/10.1161/01.CIR.101.14.1634Circulation. 2000;101:1634–1637It is now generally accepted that chronically elevated stimulation of the cardiac β-adrenergic system is toxic to the heart and that such stimulation may contribute to the pathogenesis of congestive heart failure of various causes. Administration of either β-adrenergic agonists or phosphodiesterase inhibitors has been shown to decrease survival of patients with chronic heart failure, even though they produce immediate and long-term hemodynamic benefits.1 Moreover, in human heart failure, as well as in several animal models, elevated circulating catecholamines lead, via various compensatory mechanisms, to decreased levels and functional activity of cardiac β1-adrenergic receptors (β1ARs) and thus to marked desensitization of the heart to inotropic β-adrenergic stimulation.2These biochemical and physiological changes appear to be mediated by elevated levels of the enzyme βAR kinase1 (βARK-1, GRK2) in the heart that are invariably associated with dampened responsiveness to catecholamine stimulation.3 βARK is one of a family of enzymes (G protein–coupled receptor kinases) that phosphorylate βARs and other G protein–coupled receptors after they have been stimulated, thus leading to their desensitization.4 Currently, it is widely believed that these mechanisms protect the heart from the toxic effects of inotropic β-adrenergic support. The recent success of β-blockers in treating chronic heart failure is generally explained by their ability to block the noxious effects of chronic endogenous sympathetic stimulation of the failing heart. In contrast, infusion of β-adrenergic agonists is used solely for short-term and palliative inotropic support.Given these findings, it is not surprising that there has been little recent interest in therapeutic strategies that aim to facilitate or augment signaling through β-adrenergic–coupled systems in the failing heart. All such approaches, it is generally assumed, must lead to negative consequences for the heart. Such assumptions have gained support from animal studies that demonstrate that even very modest transgenic overexpression of β1ARs in the hearts of mice leads to early and marked cardiomyopathy.5 In addition, cardiac transgenic overexpression of the α-subunit of the heterotrimeric G protein Gs also leads to a cardiomyopathic phenotype.6 It is against this background that an article in this issue by Liggett et al7 highlights several misconceptions and unfounded assumptions about β-adrenergic stimulation of the heart and points the way toward a more rational reconsideration of the potential for manipulating β-adrenergic signaling in the heart for therapeutic gain.The first widely held erroneous assumption, and the one most directly addressed by Liggett et al, is that β1ARs and β2ARs are essentially equivalent in their signaling properties and hence in the consequences of their activation. However, in striking contrast to the early cardiomyopathy resulting from even low-level (≈5-fold) transgenic overexpression of β1ARs in the heart recently reported by Engelhardt et al,5 Liggett et al now demonstrate that up to 100-fold overexpression of β2ARs in the mouse heart causes significantly increased cardiac contractile force without any cardiomyopathic consequences during the 1-year study period.7 (Recall that 1 year is approximately half the normal life span of a mouse.) Only at even higher levels of overexpression (up to 350-fold) were pathological changes observed. Are these results surprising?In fact, they are not. The first study of transgenic overexpression of a βAR in the mouse heart by Milano et al8 reported very high levels of expression of the β2AR (up to 200-fold), similar to the higher-expressing lines of Liggett et al. These animals had remarkably elevated contractility unresponsive to further β-adrenergic stimulation. Like the highest-expressing lines of Liggett et al, the inotropic effect in these animals appeared to be due to the constitutive activity of the highly expanded pool of receptors and could not be reduced by conventional β-blockers such as propranolol. These animals still displayed markedly elevated cardiac contractility at 1 year of age and developed mild fibrosis late in life (≥1 year),9 as would be expected from the dose-response curves for receptor expression now provided by Liggett et al.7 The Liggett group also reported a transgenic mouse expressing β2ARs at much lower levels of expression (≈15-fold). Even at these very low levels, marked potentiation of catecholamine-stimulated inotropy was observed, with no pathological consequences.10Other findings also indicate that the consequences of β1- and β2-adrenergic stimulation in the heart are quite different. Although both receptors classically activate adenylate cyclase via stimulation of Gs, β2-receptors can also powerfully stimulate Gi11 (the myocardial concentrations of which are elevated in CHF). This has at least 2 types of consequences. First, it limits the extent of the contractile response to overexpressed β2ARs, as in the animals reported by Milano et al8 (because Gi inhibits adenylate cyclase). Only when Gi proteins were inactivated by pertussis toxin treatment did these transgenically overexpressed β2ARs fully stimulate contractility.11 Second, activation of Gi has the potential to couple these receptors to other important signaling pathways, such as the MAP kinases.12 Cardiac β1ARs and β2ARs have also been shown to differ in their effects on contraction, cytosolic Ca2+ concentrations, and Ca2+ currents in isolated rat ventricular cells.13That β1ARs and β2ARs should display distinctly different signaling patterns is predictable from their molecular structures. Both are heptahelical or 7-membrane-span receptors. Greatest amino acid identity is present in the transmembrane regions (≈71%), which determine the specificity of ligand binding.14 However, the cytoplasmic regions of the receptors, which interact with other cellular proteins to mediate various signaling events, are considerably more divergent.14 In fact, Liggett et al have previously called attention to polyproline stretches present in the third cytoplasmic loop of β1ARs but not β2ARs.15 Swapping of this region between the β1ARs and β2ARs significantly altered their signaling properties.15 Moreover, we recently identified a novel family of the SH3 domain containing proteins that interact with the β1ARs (and not the β2ARs) via this region.16 Distinctly different proteins also interact with the β1ARs and β2ARs via protein interaction domains called PDZ domains that bind to the divergent last 4 amino acid residues of the carboxy-terminal tails of these receptors.17Recent studies have increasingly implicated the process of apoptosis, or programmed cell death, in the development of cardiomyopathy and heart failure.18 In vitro experiments with isolated cardiac myocytes,1920 as well as in vivo experiments with knockout mice lacking either β1AR, β2AR, or both (A.J. Patterson, B.K. Kobilka, personal communication, 1999), indicate that chronic catecholamine stimulation induces apoptosis or sudden death, respectively. However, these responses appear to be initiated by β1ARs, whereas β2AR stimulation either has no effect or may even be protective.1920 Thus, although both receptors are present in cardiac myocytes and mediate inotropic effects, the toxic effect of β-adrenergic stimulation appears to be mediated largely, if not exclusively, by the β1AR.Another recent line of research relevant to issues raised in the article by Liggett et al concerns the consequences of lowering the elevated levels of cardiac βARK-1 activity generally found in human heart failure or in animal models of the disease. Lowering of βARK-1 activity in the heart presumably would enhance signaling through not only βARs but other G protein–coupled receptors as well. As shown in animal models of several cardiac disorders, cardiac βARK-1 levels rise early, before marked cardiac deterioration and desensitization occur, presumably in response to the increased sympathetic stimulation that accompanies heart failure.21 Moreover, 3-fold transgenic overexpression of βARK in the mouse heart (a level comparable to that observed in heart failure) reproduces the marked biochemical and physiological desensitization to β-adrenergic stimulation observed in heart failure.22What are the physiological effects of lowering cardiac βARK activity? One approach lowered βARK activity by transgenic overexpression of an inhibitory peptide derived from the carboxy-terminus of βARK. This peptide blocks the interaction of endogenous βARK with Gβγ, preventing agonist-induced translocation of the enzyme to the plasma membrane.22 A second approach was to knock out a single βARK allele by homologous recombination.23 In both models, reduction in myocardial βARK activity increased basal and isoproterenol-stimulated myocardial contractility in vivo. When these 2 mouse lines were crossed to produce animals with even lower myocardial βARK-1 activity, contractility rose even more.23 These data suggest that βARK-1–mediated desensitization of βARs and perhaps other G protein–coupled receptors acts as a brake on myocardial contractility. Of course, other, as yet undefined, activities of βARK might also be involved. Animals with reduced cardiac βARK activity and increased myocardial contractility have normal life spans, with no cardiac pathological conditions detectable at any point.22Therapeutic ImplicationsThe observations summarized above, indicating that increased β2AR activity or reduction in βARK levels can improve myocardial performance without noxious effects on the heart, call into question the widely held notion that any maneuver that chronically augments β-adrenergic signaling in the heart will have deleterious consequences. They also immediately suggest several novel therapeutic strategies for the treatment of heart failure, some of which are currently being tested in animal models.β2-Adrenergic ReceptorsCan overexpression of β2ARs (a possible future target of gene therapy) improve cardiac performance in the setting of heart failure without causing negative effects? The question is being approached in several ways. One is to cross animals overexpressing β2ARs in the heart with genetically engineered lines of mice that develop heart failure.2425 An important caveat in this approach is that, as described above, many of the lines of transgenic βAR-overexpressing mice described thus far express the receptors at extraordinarily high levels, well beyond the therapeutic window delineated by Liggett et al.7 In fact, when a transgenic animal model of hypertrophic cardiomyopathy with heart failure (overexpression of the α-subunit of the heterotrimeric G protein Gq) was made to coexpress the β2AR at relatively low levels, improved myocardial performance was observed, whereas at higher levels, deterioration was observed.25 Very high levels of transgenic β2AR overexpression did not improve another genetic mouse model of heart failure (MLP knockout).24 However, as delineated by Liggett et al, such studies need to be performed in the future with much lower levels of β2AR expression.Another approach has been to transfer the β2AR with adenoviral vectors. Enhanced function of cultured cardiac myocytes isolated from failing rabbit hearts has been achieved via gene transfer, leading to expression levels ≈15-fold above normal.26 In addition, by use of a catheter-based technique for delivery of an adenovirus containing the human β2AR transgene to the rabbit coronary circulation in vivo27 or by delivering the β2AR virus to heterotopically transplanted rat hearts, global myocardial expression of receptor was achieved at levels 5- to 10-fold above normal.28 Strikingly, this was sufficient to raise basal and isoproterenol-stimulated cardiac contractility. These studies underscore the potential feasibility of a gene therapy approach with β2ARs. They also highlight an apparently broad therapeutic window, because at least 10- to 20-fold higher levels of transgenic overexpression than were functionally effective in these adenoviral studies in rat and rabbit were necessary to observe any chronic cardiotoxicity.βARK InhibitionTransgenic overexpression of a βARK inhibitor peptide largely reverses the impaired cardiac performance in both the MLP knockout mouse24 and the calsequestrin-overexpression mouse models of heart failure.29 In the latter model, not only is cardiac function improved but survival time is approximately doubled with the βARK inhibitor peptide. In both cases, the markedly blunted β-adrenergic responsiveness of the heart is reversed and the elevated βARK levels are lowered toward normal. In another example, the blunted cardiac response to isoproterenol and elevated cardiac βARK activity in transgenic mice overexpressing βARK in the heart are both reversed when these animals are mated with mice expressing the βARK inhibitor peptide in the heart.30 These results directly demonstrate that the ability of the βARK inhibitor to increase cardiac responsiveness to catecholamines (endogenous and exogenous) is, in fact, associated with its ability to inhibit the enzyme in vivo.In vitro, adenovirus-mediated transfer of the βARK inhibitor peptide into cardiac myocytes derived from rabbits previously paced into ventricular failure has also been shown to restore β-adrenergic–responsive cAMP accumulation to normal.26 A caveat to the interpretation of these studies, however, is that the βARK inhibitor peptide works by blocking Gβγ interaction with the enzyme. Because Gβγ undoubtedly plays a variety of other signaling roles in the heart, the possibility remains that the βARK inhibitor peptide in fact has activities unrelated to βARK inhibition.One case in which βARK inhibition has not reversed deteriorating cardiac function is the previously mentioned Gαq-overexpressing mouse with hypertrophy and heart failure.25 However, it should be noted that unlike the other models cited, and in fact most cases of human heart failure, these animals do not display elevated cardiac βARK activity or downregulated cardiac βARs.Taken together, these results suggest that inhibition of cardiac βARK activity, either by gene transfer or more directly by the development of suitable inhibitor drugs, may represent a novel approach to the treatment of heart failure. The concern about such an approach has stemmed from the notion that elevated myocardial βARK levels and the resulting desensitization of cardiac βARK are purely protective mechanisms. Abrogation of such compensatory mechanisms, it has been reasoned, would surely only worsen the physiological deterioration caused by excess catecholamine stimulation. However, as demonstrated above, when this notion is directly tested in animal models, it is found not to be so. Inhibition of elevated βARK activity by blockade of Gβγ interactions in several animal models of heart failure leads to reversal of desensitization and improved cardiac performance and longevity.2429 These findings, in turn, suggest that elevated βARK activity and desensitization are, at least in some respects, maladaptive in the failing heart. Thus, the best strategy for developing potentially useful βARK inhibitors may be to target the Gβγ-βARK interaction.How can one reconcile a potential role for augmentation of β2AR signaling or for βARK inhibition in heart failure with the well-established findings that β-adrenergic agonist therapy, although of short-term benefit, does not improve long-term outcomes1 and with the recent success of β-blocker31 therapy for heart failure? The answer appears to lie in the very different consequences of each of these means of augmenting β-adrenergic stimulation of the heart. Chronic catecholamine (agonist) stimulation of the heart demonstrably has deleterious effects, which appear to be mediated largely via β1ARs. The concept of inotropic gene therapy with β2ARs appears to circumvent these negative effects by engaging a distinct portfolio of signaling pathways that lack the apoptotic and perhaps some of the arrhythmogenic potential of β1AR stimulation.Inhibitors of βARK increase contractility in several animal models of heart failure without any evidence of pathological consequences even over very long periods.2429 This is in striking contrast to the effects of chronic stimulation of β1ARs5 or Gsα.6 This may be due to facilitation of cardiac support mediated by the normal ebb and flow of endogenous catecholamines (which is blocked by desensitization in heart failure) and perhaps by other, as yet unspecified, endogenous G protein–coupled receptor agonists (βARK activity is not limited to βARs).4 It is striking that βARK inhibition shares with other pharmacological therapies known to improve heart failure (eg, β-blockers) the ability to normalize or remodel signaling through the cardiac β-adrenergic system by reducing desensitization, lowering cardiac GRK activity,32 enhancing catecholamine sensitivity, and raising levels of β1ARs. Thus, it is plausible that the salutary effects of β-blockers in chronic treatment of heart failure may be due, at least in part, to their demonstrated ability to reduce the elevated levels of myocardial βARK.With recent landmark trials showing beneficial effects of β-blockers in the treatment of chronic heart failure,33 it is natural to ask why anyone would want to augment βAR signaling with a βARK inhibitor. However, given the experimental data showing the remarkable salutary effects of the βARK inhibitory peptide on reversing βAR desensitization, it becomes apparent that β-blocker therapy and βARK inhibition may in fact be complementary therapeutic modalities. For example, whereas treatment with β-blockers will antagonize the catecholamine toxicity associated with heart failure, βARK inhibition will act to preserve normal βAR–G protein coupling in times of need, such as during exercise and periods of stress. Thus, there are likely to be major differences between the deleterious effects of chronic βAR stimulation and the potentially beneficial effects of intermittent βAR stimulation.Twenty years ago, the idea that β-adrenergic antagonists could be used as therapeutic agents to treat heart failure was viewed as quite heretical, even though clinical data to support this were already emerging.34 Almost 2 decades was necessary to reverse the well-established, although erroneous, conventional wisdom on this point and bring these drugs into the therapeutic armamentarium for the treatment of heart failure. Given the rapid pace of current experimental efforts, a much more rapid assessment of β2AR augmentation and βARK inhibition as novel therapeutic modalities in heart failure seems likely. Testing of the latter therapeutic target would be greatly facilitated by the development of small-molecule inhibitors of the βARK-Gβγ interaction.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Robert J. Lefkowitz, HHMI, Duke University Medical Center, Box 3821, Durham, NC 27710. E-mail [email protected] References 1 Packer M. The development of positive inotropic agents for chronic heart failure: how have we gone astray? J Am Coll Cardiol. 1993;22(suppl A):119A–126A.Google Scholar2 Fowler MB, Laser JA, Hopkins GL, Minobe W, Bristow MR. Assessment of the β-adrenergic receptor pathway on the intact failing human heart: progressive receptor down regulation and subsensitivity to agonist response. Circulation.1986; 74:1291–1301.Google Scholar3 Koch WJ, Milano CA, Lefkowitz RJ. Transgenic manipulation of myocardial G protein–coupled receptors and receptor kinases. 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Circulation.2000; 101:1707–1714.CrossrefMedlineGoogle Scholar8 Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ. Markedly enhanced myocardial function in transgenic mice with cardiac overexpression of the human beta2-adrenergic receptor. Science.1994; 264:582–586.CrossrefMedlineGoogle Scholar9 Koch WJ, Lefkowitz RJ, Rockman HA. Functional consequences of altering myocardial adrenergic receptor signaling. Annu Rev Physiol..2000; 62:237–260.CrossrefMedlineGoogle Scholar10 Turki J, Lorenz JN, Green SA, Donnelly ET, Jacento M, Liggett SB. Proc Natl Acad Sci U S A.1996; 93:10483–10488.CrossrefMedlineGoogle Scholar11 Xiao RP, Avdonin P, Zhou YY, Cheng H, Akhter SA, Eschenhagen T, Lefkowitz RJ, Koch WJ, Lakatta EG. Coupling of β2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res.1999; 84:43–52.CrossrefMedlineGoogle Scholar12 Daaka Y, Luttrell LM, Lefkowitz RJ. 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Intrinsic receptor activity of β1-adrenoceptors overexpressed in rat ventricular cardiac myocytes. Circulation. 1998;98(suppl I):I-123. Abstract.Google Scholar21 Cho MC, Rapacciuolo A, Koch WJ, Kobayashi Y, Jones L, Rockman HA. Defective β-adrenergic signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. J Biol Chem.1999; 274:22251–22256.CrossrefMedlineGoogle Scholar22 Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ. Cardiac function in mice overexpressing the β-adrenergic receptor kinase or a βARK inhibitor. Science.1995; 268:1350–1353.CrossrefMedlineGoogle Scholar23 Rockman HA, Choi D-J, Akhter SA, Jaber M, Giros B, Lefkowitz RJ, Caron MG, Koch WJ. Control of myocardial contractile function by the level of β-adrenergic receptor kinase 1 in gene targeted mice. J Biol Chem.1998; 273:18180–18184.CrossrefMedlineGoogle Scholar24 Rockman HA, Chien KR, Choi D-J, Iaccarino G, Hunter JJ, Ross J Jr, Lefkowitz RJ, Koch WJ. Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A.1998; 95:7000–7005.CrossrefMedlineGoogle Scholar25 Dorn GW II, Tepe NM, Lorenz J, Koch WJ, Liggett SB. Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice. Proc Natl Acad Sci U S A.1999; 96:6400–6405.CrossrefMedlineGoogle Scholar26 Akhter SA, Skaer C, Kypson AP, McDonald PH, Peppel KC, Glower DD, Lefkowitz RJ, Koch WJ. Restoration of β-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer. 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In vivo inhibition of elevated myocardial β-adrenergic receptor kinase activity in hybrid transgenic mice restores normal β-adrenergic signaling and function. Circulation.1999; 100:648–653.CrossrefMedlineGoogle Scholar31 Feldman AM, McTiernan C. New insight into the role of enhanced adrenergic receptor-effector coupling in the heart. Circulation.1999; 100:579–582.CrossrefMedlineGoogle Scholar32 Iaccarino G, Tomhave ED, Lefkowitz RJ, Koch WJ. Reciprocal in vivo regulation of myocardial G protein–coupled receptor kinase expression by β-adrenergic receptor stimulation and blockade. Circulation.1998; 98:1783–1789.CrossrefMedlineGoogle Scholar33 CIBIS-II Investigators, and Committees. The cardiac insufficiency bisoprolol study II (CBIS-II): a randomized trial. Lancet.1999; 353:9–13.CrossrefMedlineGoogle Scholar34 Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Prolongation of survival in congestive cardiomyopathy by beta receptor blockade. 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