Cardiomyocyte Life-Death Decisions in Response to Chronic β-Adrenergic Signaling
2013; Lippincott Williams & Wilkins; Volume: 112; Issue: 3 Linguagem: Inglês
10.1161/circresaha.113.300805
ISSN1524-4571
AutoresRussell S. Whelan, Klitos Konstantinidis, Rui-Ping Xiao, Richard N. Kitsis,
Tópico(s)Phosphodiesterase function and regulation
ResumoHomeCirculation ResearchVol. 112, No. 3Cardiomyocyte Life-Death Decisions in Response to Chronic β-Adrenergic Signaling Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCardiomyocyte Life-Death Decisions in Response to Chronic β-Adrenergic Signaling Russell S. Whelan, Klitos Konstantinidis, Rui-Ping Xiao and Richard N. Kitsis Russell S. WhelanRussell S. Whelan From the Departments of Medicine (R.S.W., K.K., R.N.K.) and Cell Biology (R.S.W., K.K., R.N.K.), Wilf Family Cardiovascular Research Institute (R.S.W., K.K., R.N.K.), Diabetes Research Center (R.N.K.), and Albert Einstein Cancer Center (R.N.K.), Albert Einstein College of Medicine, Bronx, NY; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA (K.K.); and Institute of Molecular Medicine, Center for Life Sciences, Peking University, Beijing, China (R.-P.X.). , Klitos KonstantinidisKlitos Konstantinidis From the Departments of Medicine (R.S.W., K.K., R.N.K.) and Cell Biology (R.S.W., K.K., R.N.K.), Wilf Family Cardiovascular Research Institute (R.S.W., K.K., R.N.K.), Diabetes Research Center (R.N.K.), and Albert Einstein Cancer Center (R.N.K.), Albert Einstein College of Medicine, Bronx, NY; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA (K.K.); and Institute of Molecular Medicine, Center for Life Sciences, Peking University, Beijing, China (R.-P.X.). , Rui-Ping XiaoRui-Ping Xiao From the Departments of Medicine (R.S.W., K.K., R.N.K.) and Cell Biology (R.S.W., K.K., R.N.K.), Wilf Family Cardiovascular Research Institute (R.S.W., K.K., R.N.K.), Diabetes Research Center (R.N.K.), and Albert Einstein Cancer Center (R.N.K.), Albert Einstein College of Medicine, Bronx, NY; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA (K.K.); and Institute of Molecular Medicine, Center for Life Sciences, Peking University, Beijing, China (R.-P.X.). and Richard N. KitsisRichard N. Kitsis From the Departments of Medicine (R.S.W., K.K., R.N.K.) and Cell Biology (R.S.W., K.K., R.N.K.), Wilf Family Cardiovascular Research Institute (R.S.W., K.K., R.N.K.), Diabetes Research Center (R.N.K.), and Albert Einstein Cancer Center (R.N.K.), Albert Einstein College of Medicine, Bronx, NY; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA (K.K.); and Institute of Molecular Medicine, Center for Life Sciences, Peking University, Beijing, China (R.-P.X.). Originally published1 Feb 2013https://doi.org/10.1161/CIRCRESAHA.113.300805Circulation Research. 2013;112:408–410is corrected byCorrectionIntroductionβ-adrenergic signaling in the heart is a double-edged sword. In the short-term, it enhances cardiac function, whereas chronic high-level activation results in heart failure. In this issue of Circulation Research, Zhang et al1 investigate mechanisms that mediate β-adrenergic–induced cell death and, in doing so, uncover a survival pathway of potential clinical relevance.Article, see p 498A basic principle of cardiac pharmacology is that acute activation of β-adrenergic receptors (referred to herein as β-receptors) increases heart rate (chronotropy), contractility (inotropy), and relaxation of heart muscle (lusitropy) to augment cardiac systolic and diastolic performance. These responses couple cardiac function with physiological demands, such as exercise, and provide compensatory mechanisms when the circulation is threatened by insults, such as hemorrhage or sudden deterioration in cardiac function. The major ligand in this context is norepinephrine, a catecholamine derived primarily from the postganglionic sympathetic neurons that innervate the heart and, to a lesser extent, from the adrenal medulla.Given the beneficial hemodynamic effects of acute β-adrenergic signaling, cardiologists in the 1980s hypothesized that activation of this pathway may benefit patients with advanced heart failure, a condition with an astounding 5-year mortality of ≈50%. Indeed this approach improved cardiac hemodynamics in the short term, but it soon became apparent that chronic treatment results in marked increases in patient mortality.2 Conversely, β-receptor blockade reduced mortality,3 a finding presaged by small studies decades earlier.4 These paradoxical findings were at odds with the accepted notion that improvement of hemodynamics alone should be sufficient to stem the progression of heart failure. The resolution of these data ultimately necessitated a new paradigm. In this model, catecholamines initially help the failing heart to compensate for decreased pump function. However, when present chronically at high levels, they function as toxins that promote adverse cardiac remodeling and progressive deterioration of function.How does chronic β-adrenergic stimulation damage the heart? This is thought to occur through dysfunction of viable cardiomyocytes (eg, abnormalities in Ca2+ handling)5 and cell death. Cardiomyocytes may die via apoptosis, necrosis, or perhaps autophagy. Multiple genetic and pharmacological studies in cells and intact mice indicate that the β1-receptor working through Gαs not only mediates acute increases in chronotropy and inotropy but, when activated chronically, also plays the primary role in cell death6–11 (Figure). In contrast, some data indicate that the β2-receptor may signal survival when its coupling switches from Gαs to Gαi.Download figureDownload PowerPointFigure. Chronic β1-adrenergic receptor activation induces cardiomyocyte death. The binding of a β-adrenergic ligand to the β1-receptor activates adenyl cyclase through Gαs resulting in the production cAMP. The binding of 2 cAMP molecules to each of the protein kinase A (PKA) regulatory subunits (R) releases the catalytic subunits (C), which are enzymatically active after the binding of ATP. PKA phosphorylates many targets including the L-type calcium channel resulting in the entry of Ca2+ into the cytoplasm. Increases in intracellular Ca2+ activate calmodulin-dependent protein kinase II (CaMKII). PKA and CaMKII phosphorylate phospholamban relieving its inhibition of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), thereby resulting in the entry of Ca2+ into the sarcoplasmic reticular (SR) lumen. When signaling is sustained, the SR becomes Ca2+-overloaded resulting in the induction of apoptosis and necrosis through a variety of mechanisms (not shown). cAMP also binds to and activates exchange protein directly activated by cAMP (EPAC), leading to a cascade (not shown) that activates extracellular signal-related kinase (ERK), which signals cell survival. Note that the events depicted are highly simplified. PLB indicates phospholamban; PKI, protein kinase inhibitor of PKA (see text); 8-cp-TOME, small molecule activator of EPAC; and PD98059, small molecule that inhibits ERK activation.Although it is clear that chronic β1-receptor activation induces cell death, considerable controversy has surrounded the mechanism. The major bone of contention has been whether protein kinase A (PKA) plays a critical role. Inactive PKA is composed of 2 inhibitory subunits bound to 2 catalytic subunits. The binding of 2 cAMP molecules to each of the regulatory subunits releases the catalytic subunits, which then become enzymatically active after the binding of ATP. Although the liganding of agonists to the β-receptor activates PKA, the question is whether PKA activation is needed for killing in cardiomyocytes.Initial investigations, using H89 or KT5720, small molecules that competitively inhibit the binding of ATP to the catalytic subunits, found that β-adrenergic–induced death of isolated neonatal and adult rat cardiomyocytes is dependent on PKA.7,8 Unfortunately, H89 and KT5720 are now recognized to have multiple off-target effects, including inhibition of other kinases and even β-adrenergic receptors.12A subsequent study used more specific approaches to inhibit PKA:13 Rp-8-CPT-cAMPS, which competitively inhibits cAMP binding to PKA regulatory subunits; and PKI, a peptide derived from an endogenous protein inhibitor of PKA that binds the catalytic subunits at the site occupied by the regulatory subunit in the inactive state.14 These independent approaches demonstrated the PKA independence of β-adrenergic–induced death.Zhang et al1 addresses this issue for the first time in vivo, using mice that express an inducible, cardiomyocyte-specific PKI-GFP transgene. Isolated adult feline cardiomyocytes were also studied using adenoviral-mediated gene transfer. In both contexts, β-adrenergic–induced cardiomyocyte death was found to be dependent on PKA over a range of acute and chronic time points. In addition, inhibition of PKA in the transgenic mice abrogated β-adrenergic–induced increases in cardiac hypertrophy and fibrosis and decreases in systolic function. Although the conclusions of the in vivo and cell culture experiments in this study are concordant, they are opposite to the results of the cell culture experiments in the PKI study described above, which found that β-adrenergic–induced killing was PKA-independent.13 A potential explanation for this discrepancy is that the PKI constructs in these studies were not identical. Although both peptides were successful in inhibiting endogenous PKA activity, it is theoretically possible that they differ with respect to other biological effects. A more obvious difference, however, is the species of the cultured cardiomyocytes used—adult cat in the current study versus adult mouse in the previous one. It is possible that the higher levels of cytosolic Ca2+ in unpaced isolated murine cardiomyocytes15 lower the threshold for cell death, thereby bypassing the requirement for PKA. Future experiments could test alternative strategies to inhibit PKA, such as other dominant negative alleles and simultaneous knockdown of the isoforms of the catalytic subunits. However, given that the possible discrepancy in PKA dependence may be attributable to species differences, it might be most informative to conduct studies in a more clinically relevant species, such as the pig, using pharmacological and in vivo viral gene transfer approaches.The present study goes on to address events downstream of PKA. In agreement with previous work,13 intracellular Ca2+ and Ca2+/calmodulin-dependent protein kinase II play important roles in β-adrenergic–induced cardiomyocyte killing. Mechanisms linking PKA with calmodulin-dependent protein kinase II remain controversial, however. This study presents pharmacological evidence that calmodulin-dependent protein kinase II activation in response to β-agonists requires PKA-stimulated increases in Ca2+ influx through L-type calcium channels. In accordance with this model, PKI blocks these increases. The investigators also found that increases in sarcoplasmic reticular [Ca2+] seem to be particularly important in β-adrenergic–induced cell death. Although this sarcoplasmic reticular Ca2+-overload model is consistent with mechanisms of cardiomyocyte apoptosis and necrosis in other settings, it also needs to be considered in the context of data demonstrating that long-term β-adrenergic stimulation depletes the sarcoplasmic reticular of Ca2+.5 Insights into this conundrum may be provided by a more precise delineation of the time course of sarcoplasmic reticular [Ca2+] during β-stimulation.Perhaps, the most exciting aspect of Zhang et al1 is the identification of a β-adrenergic–induced survival pathway. Exchange protein directly activated by cAMP (EPAC)16 is a guanine nucleotide exchange protein for the small GTPases, Rap1 and Rap2. As its name indicates, it is activated by cAMP, independently of PKA. Although prior work has shown that EPAC can promote or inhibit cell death depending on the cellular context, it seems to promote survival in cardiomyocytes. By using PKI to block the PKA-mediated death arm of the pathway, this study reveals that β-adrenergic stimulation activates EPAC and promotes cardiomyocyte survival in a manner dependent on extracellular signal-related kinases (ERKs). Although the necessity of EPAC for these survival effects still requires testing, its sufficiency was demonstrated using 8-cp-TOME, a cAMP analogue that directly activates EPAC. These cell culture findings were then taken to a mouse model of postmyocardial infarction heart failure. PKI-mediated inhibition of PKA was more effective in preserving cardiac function 4 weeks after infarction than was metoprolol (a β1-specific antagonist), suggesting that targeted inhibition of the PKA-dependent death pathway is superior to ablation of both death and survival pathways downstream of the β1-receptor.What are the potential clinical implications of these data? While one might consider substituting peptide or small molecule inhibitors of PKA for β1-blockers in the treatment of postmyocardial infarction heart failure, it must be kept in mind that β-blockers provide beneficial effects beyond those considered here. A more attractive option might be to supplement β-blockade with a small molecule activator of the EPAC-ERK pathway.Zhang et al1 have provided critical insights into the bigger picture of cardiomyocyte life-death decisions resulting from chronic β-adrenergic stimulation. The hypotheses generated by these data may provide important opportunities for clinical translation.AcknowledgmentsWe thank Andrew R. Marks, Evangelia Kranias, Alexander Kushnir, Joan Heller Brown, and W. Jonathan Lederer for helpful discussions.Sources of FundingThis work was supported by grants to R.N. Kitsis from the National Institutes of Health (5R01HL060665-14, 1R03DA031671-02, 5U01HL099776-04) and The Harrington Project for Discovery and Development. R.N. Kitsis is supported by the Dr Gerald and Myra Dorros Chair in Cardiovascular Disease. We are most grateful to the Wilf Family for their ongoing generosity and support.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Richard N. Kitsis, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail [email protected]References1. Zhang X, Szeto C, Gao E, et al. Cardiotoxic and cardioprotective features of chronic β-adrenergic signaling.Circ Res. 2013; 112:498–509LinkGoogle Scholar2. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.N Engl J Med. 1991; 325:1468–1475.CrossrefMedlineGoogle Scholar3. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. 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Related articlesCorrectionCirculation Research. 2013;112:e181-e181 February 1, 2013Vol 112, Issue 3 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.113.300805PMID: 23371896 Originally publishedFebruary 1, 2013 Keywordsβ-adrenergic signalingEPACcell deathheart failurenecrosisPKAapoptosisPDF download Advertisement
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