Adrenal Signaling in Heart Failure
2013; Lippincott Williams & Wilkins; Volume: 63; Issue: 2 Linguagem: Inglês
10.1161/hypertensionaha.113.02382
ISSN1524-4563
Autores Tópico(s)Pharmacological Effects and Assays
ResumoHomeHypertensionVol. 63, No. 2Adrenal Signaling in Heart Failure Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAdrenal Signaling in Heart FailureSomething More Than a Distant Ship's Smoke on the Horizon Gaetano Santulli, MD, PhD Gaetano SantulliGaetano Santulli From the Departments of Advanced Biomedical Sciences and Translational Medical Sciences, "Federico II" University, Naples, Italy; and College of Physicians and Surgeons, Columbia University Medical Center, New York, NY Originally published11 Nov 2013https://doi.org/10.1161/HYPERTENSIONAHA.113.02382Hypertension. 2014;63:215–216Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 See related article, p 404–412Heart failure (HF) is the leading cause of mortality and morbidity in the Western world.1 The search for therapeutics to cure HF has led investigators to examine the mechanisms underlying HF, paying a particular attention to understanding the role of defects in β-adrenergic receptors (βARs) regulation in the pathophysiology of such a disease. Hence, during HF, enhanced levels of catecholamines resulting from activation of the sympathetic nervous system lead to chronic stimulation of cardiac βARs. This acute fight or flight response ensures an increase in cardiac function, to achieve an adaptation of the cardiac output to the systemic needs and somehow preserve cardiovascular homeostasis. However, long-term stimulation of the βARs becomes harmful, contributing to the progression of failure.2The heart adapts to the chronically elevated concentration of adrenalin and noradrenalin by blunting the response to agonist stimulation. Such a process, known as desensitization, is essentially mediated by βAR phosphorylation via G-protein–coupled receptor kinases (GRKs),3 followed by translocation and binding to the receptor by the multifunctional protein β-arrestin, targeting the receptor for internalization.4 Two distinct isoforms of β-arrestin are expressed in the heart, namely β-arrestin-1 and β-arrestin-2. Of interest, proteomic analyses revealed that β-arrestins directly interacts with >300 proteins from different families involved in cellular signaling. Thus, arrestin-mediated signaling encompasses manifold pathways, including kinase activation, transcriptional regulation, and receptor transactivation. The importance of β-arrestins is further evidenced by the early embryonic lethality of the double knockout mouse.4 Remarkably, the functional role of each isoform in HF had not been extensively investigated hitherto.In a noteworthy study reported in this issue of Hypertension, the group led by Dr Lymperopoulos5 elegantly shows in an in vivo model of myocardial infarction that β-arrestin-1 is detrimental for cardiac function. Intriguingly, the authors demonstrate that β-arrestin-1 plays a key role in HF pathophysiology via actions not only in the heart but also in the adrenal gland, where catecholamines are primarily produced. Indeed, genetic deletion of β-arrestin-1 (achieved by a global knockout mouse model) markedly improved cardiac function, adverse remodeling, aldosterone levels, and cardiac βAR function during HF progression.Mechanistically, the deletion of β-arrestin-1 in the adrenal glands might be responsible for the improvement in the neurohormonal profile described in these animals after myocardial infarction. However, the observed amelioration in the adrenergic and inotropic reserves can be essentially attributed to the absence of β-arrestin-1 in the heart (Figure). The authors demonstrated how to obtain both these advantages at 1 fell swoop, brilliantly exploiting the β-arrestin-1–mediated signaling in the adrenal-cardiac axis.5 Of course, this model represents a streamlined point of view of the whole story because adrenal gland is not the exclusive site of production of catecholamines.6Download figureDownload PowerPointFigure. Exemplificative model of the functional role of β-arrestin-1 and G-protein–coupled receptor kinase 2 (GRK2) in the adrenal gland and in the heart. In the adrenal medulla, β-arrestin-1 and GRK2 finely regulate the secretion of catecholamines. Indeed, they both prevent the α2-adrenergic receptor (α2AR)–mediated inhibition of catecholamines release. Furthermore, in the zona glomerulosa of the adrenal cortex, β-arrestin-1 is able to enhance aldosterone secretion via the heptahelical angiotensin II type 1 receptor (AT1R; not depicted in the figure for simplicity purposes). In the heart, β-arrestin-1 and GRK2 inhibit the β1AR-mediated inotropic effects, with detrimental results for cardiac function.Likewise, the same group had previously2 shown that turning down via a gene therapy approach the adrenal levels of GRK2, a master regulator of cardiac βAR desensitization alongside with β-arrestins,3 cardiac function after myocardial infarction was substantially improved. Ergo, modulation of βAR signaling via β-arrestin-1 and GRK2 inhibition from both the heart and the adrenal (Figure) seems to lead to a reduced neurohumoral burden, halting the myocardial adverse remodeling and increasing the inotropic reserves.There are several intriguing unanswered questions arising from this novel discovery; for instance, which is the respective role of β-arrestin-1 and β-arrestin-2, which action and effect have been frequently reported to be counteracting,2,4 in the transactivation of the epidermal growth factor receptor, alongside with its numerous and significant subsequent effects? Besides, which is the consequence of β-arrestin-1 deletion on insulin sensitivity and overall cardiac metabolism, especially in HF setting? Is β-arrestin-1 involved in lipid and glucose homeostasis and in insulin release from the pancreatic beta cell? Which is the functional link between β-arrestin-1 and the modulation of important phenomena undoubtedly evoked by myocardial infarction, including inflammation, angiogenesis, and mobilization of (bone marrow derived) stem cells (all processes intimately involved7 in the response to ischemic injury via cardiac repair and regeneration)? Another mechanism that might partake in the GRK2/β-arrestin–mediated cross talk between the adrenal gland and the heart is represented by the regulation of gene expression mediated by noncoding RNAs (in primis microRNAs). Supporting a potential role for β-arrestin-1 in the regulation of these activities, β2AR has been shown recently to partake in all the above-mentioned processes.6,8,9 Equally important, growing evidence indicates that loss or dysfunction of β-arrestin-2 results in profound disturbance of insulin signaling, thereby contributing to the development of insulin resistance and progression of diabetes mellitus.10Further insight into the complex neurohumoral mechanisms underlying HF might be gained in the future using conditional and tissue-specific knockout models (a major limitation of the study, promptly acknowledged by the authors, is actually the use of global knockout mice), focusing on the multifaceted interconnectivity of G-protein–coupled signaling. Nevertheless, this commendable work by Bathgate-Siryk et al5 may unlock the door to novel therapeutic interventions in HF. Indeed, modulation of events regulated by GRKs and β-arrestins signaling, both in the heart and in the adrenal, will certainly represent a more than promising strategy for the development of powerful new therapies to treat patients with failing hearts, with the auspicious potential of complementing β-blocker treatment, hampered by its negative inotropic effect.Sources of FundingDr Santulli is supported by the American Heart Association (AHA13-16810041).DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Gaetano Santulli, College of Physicians and Surgeons, Columbia University, Russ Berrie Medical Pavilion, 1150 Saint Nicholas Ave, Suite 513, New York, NY 10032. E-mail [email protected]References1. Santulli G. Epidemiology of cardiovascular disease in the 21st century: updated numbers and updated facts.JCvD. 2013; 1:1–2.Google Scholar2. Lymperopoulos A, Rengo G, Funakoshi H, Eckhart AD, Koch WJ. Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure.Nat Med. 2007; 13:315–323.CrossrefMedlineGoogle Scholar3. Santulli G, Campanile A, Spinelli L, Assante di Panzillo E, Ciccarelli M, Trimarco B, Iaccarino G. G protein-coupled receptor kinase 2 in patients with acute myocardial infarction.Am J Cardiol. 2011; 107:1125–1130.CrossrefMedlineGoogle Scholar4. Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, Lefkowitz RJ. beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor.J Biol Chem. 2006; 281:1261–1273.CrossrefMedlineGoogle Scholar5. Bathgate-Siryk A, Dabul S, Pandya K, Walklett K, Rengo G, Cannavo A, de Lucia C, Liccardo D, Gao E, Leosco D, Koch WJ, Lymperopoulos A. Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via both cardiac and adrenal-dependent neurohormonal mechanisms.Hypertension. 2014; 63:404–412.LinkGoogle Scholar6. Sorriento D, Santulli G, Del Giudice C, Anastasio A, Trimarco B, Iaccarino G. Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo.Hypertension. 2012; 60:129–136.LinkGoogle Scholar7. Santulli G, Cipolletta E, Sorriento D, Del Giudice C, Anastasio A, Monaco S, Maione AS, Condorelli G, Puca A, Trimarco B, Illario M, Iaccarino G. CaMK4 gene deletion induces hypertension.J Am Heart Assoc. 2012; 1:e001081.LinkGoogle Scholar8. Wang WC, Juan AH, Panebra A, Liggett SB. MicroRNA let-7 establishes expression of beta2-adrenergic receptors and dynamically down-regulates agonist-promoted down-regulation.Proc Natl Acad Sci U S A. 2011; 108:6246–6251.CrossrefMedlineGoogle Scholar9. Santulli G, Lombardi A, Sorriento D, Anastasio A, Del Giudice C, Formisano P, Béguinot F, Trimarco B, Miele C, Iaccarino G. Age-related impairment in insulin release: the essential role of β(2)-adrenergic receptor.Diabetes. 2012; 61:692–701.CrossrefMedlineGoogle Scholar10. Zhang M, Zhu Y, Mu K, Li L, Lu J, Zhao J, Huang X, Wang C, Jia W. Loss of β-arrestin2 mediates pancreatic-islet dysfunction in mice.Biochem Biophys Res Commun. 2013; 435:345–349.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByShe G, Hou M, Zhang Y, Zhang Y, Wang Y, Wang H, Lai B, Zhao W, Du X and Deng X (2019) Gal-3 (Galectin-3) and KCa3.1 Mediate Heterogeneous Cell Coupling and Myocardial Fibrogenesis Driven by βAR (β-Adrenoceptor) Activation, Hypertension, 75:2, (393-404), Online publication date: 1-Feb-2020. Topchieva L, Balan O, Korneva V, Malysheva I and Pankrasheva K (2020) The Nitric Oxide Metabolite Level and NOS2 and NOS3 Gene Transcripts in Patients with Essential Arterial Hypertension, Biology Bulletin, 10.1134/S1062359020010161, 47:3, (247-252), Online publication date: 1-May-2020. Zhao Y, Wang C, Wang C, Hong X, Miao J, Liao Y, Zhou L and Liu Y (2018) An essential role for Wnt/β-catenin signaling in mediating hypertensive heart disease, Scientific Reports, 10.1038/s41598-018-27064-2, 8:1, Online publication date: 1-Dec-2018. Xu Y, Qiu Z, Yang R, Wu Y and Cheng X (2018) Efficacy of mineralocorticoid receptor antagonists in postmyocardial infarction patients with or without left ventricular dysfunction, Medicine, 10.1097/MD.0000000000013690, 97:51, (e13690), Online publication date: 1-Dec-2018. Li X, Che K, Wang L, Zhang T, Wang G, Pang Z, Shen H and Du J (2017) Subcellular localization of β-arrestin1 and its prognostic value in lung adenocarcinoma, Medicine, 10.1097/MD.0000000000008450, 96:45, (e8450), Online publication date: 1-Nov-2017. Liu L, Lu Y, Bi X, Xu M, Yu X, Xue R, He X and Zang W (2017) Choline ameliorates cardiovascular damage by improving vagal activity and inhibiting the inflammatory response in spontaneously hypertensive rats, Scientific Reports, 10.1038/srep42553, 7:1, Online publication date: 1-Mar-2017. Berezin A (2017) Microparticles in Chronic Heart Failure , 10.1016/bs.acc.2017.01.001, (1-41), . Im E and Kim G (2017) Relationship between sleep duration and Framingham cardiovascular risk score and prevalence of cardiovascular disease in Koreans, Medicine, 10.1097/MD.0000000000007744, 96:37, (e7744), Online publication date: 1-Sep-2017. Xing F, Chen J, Zhao B, Jiang J, Tang A and Chen Y (2017) Real role of β-blockers in regression of left ventricular mass in hypertension patients, Medicine, 10.1097/MD.0000000000006290, 96:10, (e6290), Online publication date: 1-Mar-2017. Santulli G, Lewis D and Marks A (2017) Physiology and pathophysiology of excitation–contraction coupling: the functional role of ryanodine receptor, Journal of Muscle Research and Cell Motility, 10.1007/s10974-017-9470-z, 38:1, (37-45), Online publication date: 1-Feb-2017. Ciccarelli M, Sorriento D, Coscioni E, Iaccarino G and Santulli G (2017) Adrenergic Receptors Endocrinology of the Heart in Health and Disease, 10.1016/B978-0-12-803111-7.00011-7, (285-315), . Díez J and Ruilope L (2015) Serelaxin for the treatment of acute heart failure: a review with a focus on end-organ protection, European Heart Journal - Cardiovascular Pharmacotherapy, 10.1093/ehjcvp/pvv046, 2:2, (119-130), Online publication date: 1-Apr-2016. Wang G, Wang P, Li Y, Liu W, Bai S, Zhen Y, Li D, Yang P, Chen Y, Hong L, Sun J, Chen J, Wang X, Zhu J, Hu D, Li H, Wu T, Huang J, Tan H, Zhang J, Liao Z, Yu L, Mao Y, Ye S, Feng L, Hua Y, Ni X, Zhang Y, Wang Y, Li W, Luan X, Sun X and Wang S (2016) Efficacy and Safety of 1-Hour Infusion of Recombinant Human Atrial Natriuretic Peptide in Patients With Acute Decompensated Heart Failure, Medicine, 10.1097/MD.0000000000002947, 95:9, (e2947), Online publication date: 1-Mar-2016. Santulli G and Iaccarino G (2016) Adrenergic signaling in heart failure and cardiovascular aging, Maturitas, 10.1016/j.maturitas.2016.03.022, 93, (65-72), Online publication date: 1-Nov-2016. Zhang J, Liu C, Pan C, Bai M, Zhang J, Peng Y, Zheng D and Zhang Z (2016) Effect of multiple clinical factors on recurrent angina after percutaneous coronary intervention, Medicine, 10.1097/MD.0000000000005015, 95:41, (e5015), Online publication date: 1-Oct-2016. Zhou X, Liu X, Ji W, Liu J, Guo Z, Ren D, Ma Y, Zeng S, Xu Z, Li H, Wang P, Zhang Z, Li Y, Benefield B, Zawada A, Thorp E, Lee D and Heine G (2016) The Kinetics of Circulating Monocyte Subsets and Monocyte-Platelet Aggregates in the Acute Phase of ST-Elevation Myocardial Infarction, Medicine, 10.1097/MD.0000000000003466, 95:18, (e3466), Online publication date: 1-May-2016. Sardu C, Santamaria M, Rizzo M, Barbieri M, di Marino M, Paolisso G, Santulli G and Marfella R (2016) Telemonitoring in heart failure patients treated by cardiac resynchronisation therapy with defibrillator (CRT-D): the TELECART Study, International Journal of Clinical Practice, 10.1111/ijcp.12823, 70:7, (569-576), Online publication date: 1-Jul-2016. Santulli G (2015) Sympathetic Nervous System Signaling in Heart Failure and Cardiac Aging Pathophysiology and Pharmacotherapy of Cardiovascular Disease, 10.1007/978-3-319-15961-4_5, (83-105), . Novo G, Giambanco S, Guglielmo M, Arvigo L, Sutera M, Giambanco F, Evola S, Vaccarino L, Bova M, Lio D, Assennato P and Novo S (2015) G-protein-coupled receptor kinase 5 polymorphism and Takotsubo cardiomyopathy, Journal of Cardiovascular Medicine, 10.2459/JCM.0000000000000120, 16:9, (639-643), Online publication date: 1-Sep-2015. Hsiao F, Tung Y, Chou S, Wu L, Lin C, Wang C, Lin Y, Chang C and Chu P (2015) Fixed-Dose Combinations of Renin–Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension, Medicine, 10.1097/MD.0000000000002355, 94:51, (e2355), Online publication date: 1-Dec-2015. Berezin A, Kremzer A, Martovitskaya Y, Samura T and Berezina T (2015) The predictive role of circulating microparticles in patients with chronic heart failure, BBA Clinical, 10.1016/j.bbacli.2014.11.006, 3, (18-24), Online publication date: 1-Jun-2015. Batisse-Lignier M, Pereira B, Motreff P, Pierrard R, Burnot C, Vorilhon C, Maqdasy S, Roche B, Desbiez F, Clerfond G, Citron B, Lusson J, Tauveron I and Eschalier R (2015) Acute and Chronic Pheochromocytoma-Induced Cardiomyopathies, Medicine, 10.1097/MD.0000000000002198, 94:50, (e2198), Online publication date: 1-Dec-2015. Nikkari S, Määttä K and Kunnas T (2015) Functional Inducible Nitric Oxide Synthase Gene Variants Associate With Hypertension, Medicine, 10.1097/MD.0000000000001958, 94:46, (e1958), Online publication date: 1-Nov-2015. Santulli G (2015) microRNAs Distinctively Regulate Vascular Smooth Muscle and Endothelial Cells: Functional Implications in Angiogenesis, Atherosclerosis, and In-Stent Restenosis microRNA: Basic Science, 10.1007/978-3-319-22380-3_4, (53-77), . Pecha S, Flenner F, Söhren K, Lorenz K, Eschenhagen T and Christ T (2015) β 1 Adrenoceptor antagonistic effects of the supposedly selective β 2 adrenoceptor antagonist ICI 118,551 on the positive inotropic effect of adrenaline in murine hearts , Pharmacology Research & Perspectives, 10.1002/prp2.168, 3:5, Online publication date: 1-Oct-2015. Sardu C, Marfella R and Santulli G (2014) Impact of Diabetes Mellitus on the Clinical Response to Cardiac Resynchronization Therapy in Elderly People, Journal of Cardiovascular Translational Research, 10.1007/s12265-014-9545-9, 7:3, (362-368), Online publication date: 1-Apr-2014. Jaleta G, Gudina E and Getinet W (2014) Left ventricular hypertrophy among black hypertensive patients: focusing on the efficacy of angiotensin converting enzyme inhibitors, BMC Research Notes, 10.1186/1756-0500-7-45, 7:1, Online publication date: 1-Dec-2014. Buroker N (2014) Regulatory SNPs and transcriptional factor binding sites in ADRBK1, AKT3, ATF3, DIO2, TBXA2R and VEGFA, Transcription, 10.4161/21541264.2014.964559, 5:4, (e964559), Online publication date: 8-Aug-2014. Morelli M, Shu J, Sardu C, Matarese A and Santulli G (2019) Cardiosomal microRNAs Are Essential in Post-Infarction Myofibroblast Phenoconversion, International Journal of Molecular Sciences, 10.3390/ijms21010201, 21:1, (201) Matarese A, Gambardella J, Lombardi A, Wang X and Santulli G (2020) miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1, Cells, 10.3390/cells9071621, 9:7, (1621) Lin Y, Cheng Y, Hu J, Chu L, Shyu W, Kao C, Lin T, Kuo C, Yang A and Lee S (2016) The Coexistence of Hypertension and Ovariectomy Additively Increases Cardiac Apoptosis, International Journal of Molecular Sciences, 10.3390/ijms17122036, 17:12, (2036) Moussouttas M, Mearns E, Walters A and DeCaro M (2015) Plasma Catecholamine Profile of Subarachnoid Hemorrhage Patients with Neurogenic Cardiomyopathy, Cerebrovascular Diseases Extra, 10.1159/000431155, 5:2, (57-67) February 2014Vol 63, Issue 2 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.113.02382PMID: 24218430 Originally publishedNovember 11, 2013 PDF download Advertisement SubjectsCongenital Heart DiseaseHypertension
Referência(s)