Calcineurin Inhibition as Therapy for Cardiac Hypertrophy and Heart Failure
1999; Lippincott Williams & Wilkins; Volume: 84; Issue: 6 Linguagem: Inglês
10.1161/01.res.84.6.741
ISSN1524-4571
Autores Tópico(s)Peptidase Inhibition and Analysis
ResumoHomeCirculation ResearchVol. 84, No. 6Calcineurin Inhibition as Therapy for Cardiac Hypertrophy and Heart Failure Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBCalcineurin Inhibition as Therapy for Cardiac Hypertrophy and Heart Failure Requiescat in Pace? Richard A. Walsh Richard A. WalshRichard A. Walsh From the Department of Medicine, Case Western Reserve University, University Hospitals, Cleveland, Ohio. Originally published2 Apr 1999https://doi.org/10.1161/01.RES.84.6.741Circulation Research. 1999;84:741–743Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 8, 2018: Previous Version of Record Congestive heart failure is a major public health problem that is increasing, despite a reduced incidence and prevalence of other forms of cardiovascular disease. Initially, the heart responds to diverse pathological stimuli by an increase in mass achieved principally by enlargement of terminally differentiated cardiomyocytes. The resulting augmented chamber mass provides temporary maintenance of wall stress and organ function. If the pathological stimulus is sufficiently intense or prolonged, decompensated hypertrophy characterized by diminished cardiomyocyte and organ function occurs, and the syndrome of congestive heart failure ensues.1Over the past decade, the application of molecular and cellular biological techniques to this process has begun to provide mechanistic insights into the subcellular processes responsible for impaired cardiac function in hypertrophy and failure.2 Evidence has accumulated to implicate both cell death (necrosis and apoptosis) and chamber remodeling due to alterations in the extracellular matrix in the pathogenesis of heart failure. In addition, multiple laboratories have focused on biochemical alterations intrinsic to the cardiomyocyte, such as abnormalities of calcium homeostasis, altered myofilament activation, and altered abundance or activity of sarcolemmal ion pumps and channels. In particular, a number of laboratories using a variety of in vitro and in vivo approaches have implicated changes in signal transduction pathways in the development of this pathological process. In this context, intense interest was recently evoked by the elucidation of a new cardiomyocyte signal transduction pathway that could initiate cardiac hypertrophy and failure. Molkentin et al3 demonstrated that the calcium calmodulin–dependant protein phosphatase calcineurin can activate hypertrophic signals in vitro using neonatal cardiomyocytes and in vivo using transgenic mice that overexpressed components of the pathway in a cardiac-specific postnatal manner. Inhibition of this pathway by cyclosporine in these experimental settings prevented hypertrophy and failure. Subsequently, cyclosporine administration also appeared to ameliorate the development of cardiac hypertrophy in additional lines of transgenic mice with cardiac-specific overexpression of a variety of mutant sarcomeric proteins.4 Differing perspectives on the role of the calcineurin pathway among the hierarchy of signal transduction systems from these and other recently published studies are presented as point/counterpoint articles in this issue of Circulation Research.56Of even greater interest for those in the field are original studies published in this issue of the Journal from three separate laboratories that have examined the potential role of calcineurin inhibition by cyclosporine in the prevention of cardiac hypertrophy and failure in conventional genetic and hemodynamic overload rodent models of cardiac hypertrophy. In each case, the result is negative or incomplete abrogation of the pathological process. Zhang et al7 tested the ability of the calcineurin inhibitors cyclosporin A and FK 506 to prevent pressure-overload left ventricular hypertrophy using two widely accepted rat models: the spontaneously hypertensive rat and suprarenal aortic banding. Importantly, these investigators examined multiple time points in the hypertrophy process and different times for initiation of drug administration. Despite elevated calcineurin phosphatase activity in the hearts of the two rodent hypertrophy models and nearly complete inhibition (90%) of phosphatase activity by cyclosporine in the hypertrophied myocardium of the treated groups, neither the amount of cardiac hypertrophy nor cardiac function was appreciably altered. Ding et al8 also report the effects of cyclosporine administration on the degree of pressure-overload hypertrophy induced by 4 weeks of ascending aortic banding in mice. Similar to the study presented by Zhang et al7 , this group failed to observe any increase in the amount of cardiac hypertrophy between cyclosporine-treated and control banded mice, despite similar elevations of left ventricular systolic pressure. However, in contrast to all prior studies, Ding et al8 measured a decrease in calcineurin phosphatase activity in hypertrophied compared with normal hearts that was further reduced by cyclosporine administration. Finally, Meguro et al9 report the effects of calcineurin inhibition by cyclosporine on the degree of hypertrophy produced by transverse aortic banding in mice. Calcineurin phosphatase activity in the myocardium did not differ between hypertrophied and control hearts but was depressed by cyclosporine inhibition. Cyclosporine administration modestly attenuated the degree of cardiac hypertrophy in response to pressure overload, depressed isovolumic left ventricular function, and accelerated mortality of the banded animals. The differences in these latter two mouse studies may, in part, reflect differences in mouse strains, location of the aortic band, and the numbers of mice that were used in each experimental group (much larger in the study presented by Meguro et al9 ). Two other preliminary studies also failed to demonstrate a beneficial effect of cyclosporine administration on the development of cardiac hypertrophy in the suprarenal aortic-banded rat or transverse aortic-banded mouse.1011In balance, it would appear that cyclosporine inhibition can prevent cardiac hypertrophy when it is induced by transgenic overexpression of one of the constituents of the calcium-calcineurin-NFAT3-GATA4 pathway in mice or when some mutated sarcomeric proteins are similarly overexpressed in this species. However, there are no available data that demonstrate that calcineurin inhibition can reverse cardiac hypertrophy and failure under these experimental conditions. Calcineurin inhibition fails to prevent or only modestly attenuates the development of acquired pressure-overload hypertrophy in rats and mice with no change or impaired cardiac function.Unanswered Questions and Directions for Future ResearchHow can we reconcile the striking disparity between the results derived from in vitro neonatal cardiomyocytes and in vivo transgenic studies with the disappointing results presented herein from conventional animal models of in vivo acquired or genetic rodent hypertrophy? Congestive heart failure is a clinical syndrome that represents the final common phenotype of diverse pathological stimuli. It is unlikely that any single molecular or biochemical event will explain its common forms. Instead, investigators will pursue hierarchical mechanisms that may or may not be targets for drug development. The initial appeal for a primary role of the calcineurin pathway in cardiac hypertrophy and failure was derived from multiple clinical studies that have demonstrated elevated basal calcium levels in cardiomyocytes enzymatically extracted from hearts of patients with clinical congestive heart failure2 and the fact that this phosphatase is calcium dependent. However, none of the available studies has measured basal or cyclic calcium levels in the various model systems in which this pathway has been examined in the myocardium. There are also no available data regarding the role of the calcineurin pathway in volume-overload hypertrophy, ischemic models of cardiomyopathy, or myocarditis, in which T-cell activation may play a more prominent role. Experience with other putative mediators of cardiac hypertrophy and failure has taught us that there may be striking model-, species-, and/or cardiac chamber–specific differences.12 Only after such studies are completed will we definitively understand what role, if any, calcineurin-NFAT3-GATA4 activation plays in the development of clinically relevant cardiac hypertrophy and failure. In this regard, it will also be critically important to determine whether and to what extent calcineurin activation occurs in human cardiomyopathic heart failure.One final problem with all available studies is the use of cyclosporine and FK 506 to inhibit the calcineurin pathway. Recently, Hojo et al13 have demonstrated that cyclosporine may directly induce cancer progression (a well-known complication of this form of immunosuppressive therapy after orthotopic transplantation) by stimulating the production of transforming growth factor-β (TGF-β). Although the mechanism for enhanced TGF-β production is unknown, the cardiotrophic effects of this growth factor may offset the results of cyclosporine inhibition of calcium-calcineurin-NFAT3-GATA4 in vivo.The evolving information regarding the potential role of the calcineurin pathway in the production of cardiac hypertrophy and failure illustrates the importance of multidisciplinary studies in this arena. Use of neonatal cardiomyocytes, genetically engineered mice, and conventional experimental animal models and analysis of cardiomyopathic human tissues each has its advantages and disadvantages. Evidence for a mechanism that is present from each approach is more compelling than a role from any one approach taken in isolation. For example, recent studies in neonatal cardiomyocytes, genetically engineered mice, and human cardiomyopathic tissue suggest a potential role for protein kinase C activation in the development of cardiac hypertrophy, contractile depression, and heart failure.141516171819The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Richard A. Walsh, MD, Department of Medicine, Case Western Reserve University, University Hospitals, 11100 Euclid Ave, LKS-5029, Cleveland, OH 44106-5029. References 1 Walsh RA, Dorn GW II. Growth and hypertrophy of the heart and blood vessels. In: Alexander W, Schlant RC, Fuster V, O'Rourke RA, Roberts R, Sonnenblick EH, eds. Hurst's the Heart: Arteries and Veins. 9th ed. New York, NY: McGraw-Hill; 1997:155–168.Google Scholar2 Wagoner LE, Walsh RA. The cellular pathophysiology of progression to heart failure. Curr Opin Cardiol.1996; 11:237–244.CrossrefMedlineGoogle Scholar3 Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell.1998; 93:215–228.CrossrefMedlineGoogle Scholar4 Sussman MA, Lom HW, Gude N, Taigen T, Olson EN, Robbins J, Colbert MC, Gualberto A, Wieczorek DF, Molkentin JD. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science.1998; 281:1690–1693.CrossrefMedlineGoogle Scholar5 Olson EN, Molkentin JD. Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype? Circ Res.1999; 84:623–632.CrossrefMedlineGoogle Scholar6 Sugden PH. Signaling in myocardial hypertrophy: life after calcineurin? Circ Res.1999; 84:633–646.CrossrefMedlineGoogle Scholar7 Zhang W, Kowal RC, Rusnak F, Sikkink RA, Olson EN, Victor RG. Failure of calcineurin inhibitors to prevent pressure-overload left ventricular hypertrophy in rats. Circ Res.1999; 84:722–728.CrossrefMedlineGoogle Scholar8 Ding B, Price RL, Borg TK, Weinberg EO, Halloran PF, Lorell BH. Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin. Circ Res.1999; 84:729–734.CrossrefMedlineGoogle Scholar9 Meguro T, Hong C, Asai K, Takagi G, McKinsey TA, Olson EN, Vatner SF. Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure. Circ Res.1999; 84:735–740.CrossrefMedlineGoogle Scholar10 Luo Z, Shyu K-G, Gualberto A, Walsh K. Calcineurin inhibitors and cardiac hypertrophy. Nat Med.1998; 4:1092–1093. Letter.CrossrefMedlineGoogle Scholar11 Müller JG, Nemoto S, Laser M, Carabello BA, Menick DR. Calcineurin inhibition and cardiac hypertrophy. Science.1998; 282:1007a. Available at: http://www.sciencemag.org/cgi/content/full/282/5391/1007a.CrossrefGoogle Scholar12 Walsh RA. Microtubules and pressure-overload hypertrophy. Circ Res.1997; 80:295–296. Editorial.CrossrefMedlineGoogle Scholar13 Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature.1999; 397:530–534.CrossrefMedlineGoogle Scholar14 Paul K, Ball NA, Dorn GW II, Walsh RA. Left ventricular stretch stimulates angiotensin II–mediated phosphatidylinositol hydrolysis and protein kinase C ε isoform translocation in adult guinea pig hearts. Circ Res.1997; 81:643–650.CrossrefMedlineGoogle Scholar15 Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD, Walsh RA, King GL. Targeted overexpression of protein kinase C β2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci U S A.1997; 94:9320–9325.CrossrefMedlineGoogle Scholar16 Takeishi Y, Chu G, Kirkpatrick DM, Li A, Wakasaki H, Kranias EG, King GL, Walsh RA. In vivo phosphorylation of cardiac troponin I by protein kinase Cβ2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J Clin Invest.1998; 102:72–78.CrossrefMedlineGoogle Scholar17 Takeishi Y, Bhagwat A, Ball NA, Kirkpatrick DL, Periasamy M, Walsh RA. Effect of angiotensin converting enzyme inhibition on protein kinase C and Ca2+ cycling proteins in pressure-overload heart failure. Am J Physiol.1999; 276:H53–H62.MedlineGoogle Scholar18 Bowling N, Walsh RA, Song G, Estridge T, Sandusky GE, Fouts RL, Mintze K, Pickard T, Roden R, Bristow MR, Sabbah HN, Mizrahi JL, Gromo G, King GL, Vlahos CJ. Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation.1999; 99:384–391.CrossrefMedlineGoogle Scholar19 Simpson PC. β-Protein kinase C and hypertrophic signaling in human heart failure. Circulation.1999; 99:334–337. Editorial.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zhang G, Zhu Z and Zhang W (2009) Inhibitory Effect of Antihypertensive Drugs on Calcineurin in Cardiomyocytes, American Journal of Hypertension, 10.1038/ajh.2008.305, 22:2, (132-136), Online publication date: 1-Feb-2009. Periasamy M (2002) Calcineurin and the Heartbeat, an Evolving Story, Journal of Molecular and Cellular Cardiology, 10.1006/jmcc.2001.1520, 34:3, (259-262), Online publication date: 1-Mar-2002. CHARRON F and NEMER M (2001) Cardiac Development and Regulation of Cardiac Transcription Heart Physiology and Pathophysiology, 10.1016/B978-012656975-9/50042-0, (705-717), . Morimoto T, Hasegawa K, Wada H, Kakita T, Kaburagi S, Yanazume T and Sasayama S (2001) Calcineurin-GATA4 Pathway Is Involved in β-Adrenergic Agonist-responsive Endothelin-1 Transcription in Cardiac Myocytes, Journal of Biological Chemistry, 10.1074/jbc.M005498200, 276:37, (34983-34989), Online publication date: 1-Sep-2001. Vogel K, Briesewitz R, Wandless T and Crabtree G (2001) Calcineurin inhibitors and the generalization of the presenting protein strategy Drug Discovery and Design, 10.1016/S0065-3233(01)56008-8, (253-291), . MEISSNER G (2001) Calcium Release from Cardiac Sarcoplasmic Reticulum Heart Physiology and Pathophysiology, 10.1016/B978-012656975-9/50028-6, (461-470), . Rusnak F and Mertz P (2000) Calcineurin: Form and Function, Physiological Reviews, 10.1152/physrev.2000.80.4.1483, 80:4, (1483-1521), Online publication date: 10-Jan-2000. MacLellan W and Schneider M (2000) Genetic Dissection of Cardiac Growth Control Pathways, Annual Review of Physiology, 10.1146/annurev.physiol.62.1.289, 62:1, (289-320), Online publication date: 1-Mar-2000. Smith R and Rhodes S (2000) Applications of developmental biology to medicine and animal agriculture Progress in Drug Research, 10.1007/978-3-0348-8391-7_7, (213-256), . Choukroun G, Hajjar R, Fry S, del Monte F, Haq S, Guerrero J, Picard M, Rosenzweig A and Force T (1999) Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH2-terminal kinases, Journal of Clinical Investigation, 10.1172/JCI6350, 104:4, (391-398), Online publication date: 15-Aug-1999. April 2, 1999Vol 84, Issue 6Article InformationMetrics © 1999 American Heart Association, Inc.https://doi.org/10.1161/01.RES.84.6.741 Originally publishedApril 2, 1999 Keywordscardiomyopathysignal transductioncyclosporine therapyPDF download Advertisement
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