© 1997 American Heart Association, Inc.
Articles |
Microtubules and Pressure-Overload Hypertrophy
Correspondence to Richard A. Walsh, MD, Director of Cardiology & Cardiovascular Center, University of Cincinnati College of Medicine, PO Box 670542, Cincinnati, OH 45267-0542 E-mail WALSHRA{at}UCBEH.SAN.UC.EDU
Key Words: cardiomyocyte • cytoskeleton • hypertrophy
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Introduction |
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 Top Introduction References |
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Cardiac hypertrophy is a process whereby an increase in chamber mass occurs largely by an increase in size of terminally differentiated cardiomyocytes in response to increased external and/or internal work. Hypertrophied cardiomyocytes have abnormal electrical and mechanical properties that underlie, at least in part, altered cardiovascular function in a variety of pathological states. In particular, heart failure of diverse origins is invariably accompanied by hypertrophy, and contractile failure appears to be an inevitable consequence of hypertrophic stimuli of sufficient severity and duration. Molecular and biochemical mechanisms that are responsible for functions of the hypertrophied cardiomyocyte are being intensively studied using genetically engineered mice, animal models of human disease, and clinical investigations. These approaches have identified important alterations in myofilament and calcium-cycling proteins, sarcolemmal ion pumps, channels, and receptors and in various signal transduction pathways of hypertrophied hearts.1
In contrast to our knowledge of the importance of alterations in proteins that actively participate in myocyte contraction, relaxation, and growth, there is less information regarding the role of cytoarchitectural components of the cardiomyocyte in normal and pathological states. The cardiomyocyte cytoskeleton is composed of myofibrillar and extramyofibrillar or cytoplasmic compartments. Biophysical interactions among sarcolemmal integrin receptors and the cytoplasmic and myofibrillar cytoskeleton are largely unknown. The myofibrillar cytoskeleton includes titin (the largest protein known and the third most abundant cardiac protein), desmin, C protein, nebulin, and vinculin.2 The extramyofibrillar cytoskeleton of all eukaryotic cells, including the cardiomyocyte, is composed of an intertwined network of three classes of filamentous biopolymers: actin-containing microfilaments, intermediate filaments, and microtubules.3 Microtubules are polymers of 
- and ß-tubulin heterodimers that can polymerize and depolymerize to participate in multiple cellular processes, including growth and proliferation.4
In a series of elegant studies, Cooper and colleagues5 6 7 have unambiguously established the importance of an increase in the amount and polymerization status of tubulin to cardiomyocyte function consequent to acute right ventricular feline pressure overload. They demonstrated increases in tubulin at the steady state message and protein level that were associated with impaired cardiomyocyte sarcomere dynamics as assessed by laser diffraction microscopy. Decreases in the polymerization state of tubulin with colchicine (10-6 mol/L) or low temperature largely reversed these abnormalities, whereas increased stability of tubulin polymerization effected by taxol administration (10-5 mol/L) produced the opposite effect.
Tagawa et al8 in this issue of Circulation Research propose and establish that the principal mechanism for the dysfunctional effects of abnormal amounts and increased polymerization of tubulin in feline right ventricular hypertrophy appears to be an increase in cardiomyocyte stiffness and viscosity, as demonstrated by magnetic twisting cytometry. In this process, cardiomyocytes enzymatically extracted from right and left ventricles from cats that underwent pulmonary artery banding were decorated with ferromagnetic beads coated with a synthetic peptide that is specific for cell surface integrin receptors. Application of an intermittent magnetic field permitted direct measurement of the stress-strain relations from which estimates of the extramyofibrillar cell stiffness and viscosity were derived. Taken together, the study of Tagawa et al and previous studies clearly establish a critical role for alterations in amount and biophysical status of tubulin in the cardiomyocyte dysfunction observed in this model of right ventricular pressure-overload hypertrophy.
Can the dysfunctional effects of increased tubulin protein demonstrated by Tagawa et al8 be extrapolated to other forms of pressure-overload hypertrophy or to cardiac hypertrophy in general? At the present time, the answer appears to be negative. The results appear to be load, species, and chamber specific. Cooper and colleagues (Tsutsui et al5 ) have previously shown that feline volume-overload hypertrophy produced by surgical creation of an atrial septal defect fails to alter microtubule density or cardiomyocyte function despite an increase in right ventricular chamber mass similar to that which they observed with pulmonary arterial banding. Left ventricular pressure-overload hypertrophy produced by descending thoracic aortic banding in guinea pigs failed to alter the protein level of tubulin, and perfusion with colchicine (10-6 mol/L) failed to alter isovolumic left ventricular mechanics in normal ventricles, hypertrophied ventricles, or hypertrophied ventricles with contractile depression.9 Serial immunohistochemical studies in the rat revealed transient elevations of ß-tubulin after ascending aortic banding that returned to normal after 2 weeks in contrast to the prolonged elevation of ß-tubulin observed in feline acute right ventricular pressure-overload hypertrophy.10 11 12
Despite the apparent species, model, and chamber dependence of functionally significant alterations in the microtubules, feline right ventricular pressure-overload hypertrophy has been and will remain a valuable model to elucidate mechanisms responsible for functional alterations in pressure-overload hypertrophy and congestive heart failure. The study in the present issue of Circulation Research8 clearly demonstrates that alterations in the extramyofilament cytoskeletal matrix and their reversal can have profound functional consequences. The ability to modulate the amount and degree of polymerization of tubulin, the principal determinant of altered contractile function in this model, may have important therapeutic implications. Future studies of the cardiomyocyte cytoskeleton will likely focus on the role of alterations in microtubules in other mammalian species and, in particular, in human cardiac hypertrophy and congestive heart failure. In addition, critical examination of the fundamental role of alterations in titin and other myofilament cytoskeletal proteins in normal and pathological cardiac function is likely to occur. Titin is the major determinant of passive tension and restoring forces in cardiac and skeletal muscle,13 and the abundance of this protein appears to be increased in cardiac hypertrophy and failure (References 99 and 1414 and also reviewed in this issue of Circulation Research15 ).
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Wagoner LE, Walsh RA. The cellular pathophysiology of progression to heart failure. Curr Opin Cardiol. 1996;11:237-244.[Medline] [Order article via Infotrieve]
2. Maruyama K. Connectin, an elastic protein of striated muscle. Biophys Chem. 1994;50:73-85.[Medline] [Order article via Infotrieve]
3. Ingber DE. Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J Cell Sci. 1993;104:613-627.[Medline] [Order article via Infotrieve]
4. Gelfand VI, Bershadsky AD. Microtubule dynamics: mechanism, regulation, and function. Annu Rev Cell Biol. 1991;7:93-116.
5.
Tsutsui H, Ishihara K, Cooper G. Cytoskeletal role in the contractile dysfunction of hypertrophied myocardium. Science. 1993;260:682-687.
6.
Tsutsui H, Tagawa H, Kent RL, McCollam PL, Ishihara K, Nagatsu M, Cooper G. Role of microtubules in contractile dysfunction of hypertrophied cardiocytes. Circulation. 1994;90:533-555.
7.
Tagawa H, Rozich JD, Tsutsui H, Narishige T, Kuppuswamy D, Sato H, McDermott PJ, Koide M, Cooper G. Basis for increased microtubules in pressure-overload hypertrophied cardiocytes. Circulation. 1996;93:1230-1243.
8. Tagawa H, Wang N, Narishige T, Ingber DE, Zile MR, Cooper G IV. Cytoskeletal mechanics in pressure-overload cardiac hypertrophy.
9. Collins JF, Pawloski-Dahm C, Davis MG, Ball N, Dorn GW II, Walsh RA. The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. J Mol Cell Cardiol. 1996;28:1435-1443.[Medline] [Order article via Infotrieve]
10. Samuel J, Schwartz K, Lompre A, Delcayre C, Marotte F, Swinghedauw B, Rappaport L. Immunological quantitation and localization of tubulin in adult rat heart isolated myocytes. Eur J Cell Biol. 1983;31:99-106.[Medline] [Order article via Infotrieve]
11.
Rappaport L, Samuel JL, Bertier B, Bugaisky L, Marotte F, Mercadier A, Schwartz K. Isomyosins, microtubules and desmin during the onset of cardiac hypertrophy in the rat. Eur Heart J. 1984;5:243-250.
12. Samuel J, Marotte F, Delcayre C, Rappaport L. Microtubule reorganization is related to rate of heart myocyte hypertrophy in rat. Am J Physiol. 1986;251:H1118-H1125.
13.
Helmes M, Trombitás K, Granzier H. Titin develops restoring force in rat cardiac myocytes. Circ Res. 1996;79:619-626.
14. Morano I, Hadicke K, Grom S, Koch A, Schwinger RH, Bohm M, Bartel S, Erdmann E, Krause EG. Titin, myosin light chains and C-protein in the developing and failing human heart. J Mol Cell Cardiol. 1994;26:361-368.[Medline] [Order article via Infotrieve]
15.
Labeit S, Kolmerer B, Linke WA. The giant protein titin: emerging roles in physiology and pathophysiology. Circ Res. 1997;80:290-294.
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