Abstract
In addition to functional alterations, heart failure has a structural basis as well. This concerns all components of the cardiac myocytes as well as the extracellular space. Proteins of the cardiomyocyte can be subdivided in 5 different categories: 1) Contractile proteins including myosin, actin, tropomyosin and the troponins. 2) Sarcomeric skeleton: titin, myosin binding protein C, α-actinin, myomesin, and M-protein. 3) True ‘cytoskeletal’ proteins: tubulin, desmin and actin. 4) Membrane-associated proteins: dystrophin, spectrin, talin, vinculin, ankyrin and others. 5) Proteins of the intercalated disc: desmosomes consisting of desmoplakin, desmocollin, desmoglein and desmin; adherens junctions with N-cadherin, the catenins and vinculin, and gap junctions with connexin. Failing myocardium obtained from patients undergoing cardiac transplantation exhibits ultrastuctural degeneration and an altered nucleus/cytoplasm relationship. The contractile proteins and those of the sarcomeric skeleton, especially titin, are downregulated, the cytoskeletal proteins desmin and tubulin and membrane-associated proteins such as vinculin and dystrophin are upregulated and those of the intercalated disc are irregularly arranged. Elevation of cytoskeletal proteins correlates well with diastolic and contractile dysfunction in these patients. The enlarged interstitial space contains fibrosis, i.e. accumulations of fibroblasts and extracellular matrix components, in addition to macrophages and microvascular elements. Loss of the contractile machinery and related proteins such as titin and α-actinin may be the first and decisive event initiating an adaptive increase in cytoskeleton and membrane associated components. Fibrosis may be stimulated by subcellular degeneration. The hypothesis is put forward that all proteins of the different myocardial compartments contribute to the deterioration of cardiac function in heart failure.
Similar content being viewed by others
References
Starling RC. The health-care impact of heart failure. In: Topol EJ, ed. Textbook of Cardiovascular Medicine Philadelphia: Lippincott-Raven; 1998:2205-2214.
Braunwald E. Pathophysiology of heart failure. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine Philadelphia: W.B. Saunders; 1980:453-483.
Bristow MR, Ginsburg R, Minobe W. Decreased catecholamine sensitivity and β-adrenergic receptor density in failing human hearts. N Engl J Med 1982;307:205-211.
Bristow MR, Port JD, Sandoval AB, Rasmussen R, Ginsburg R, Feldman AM. β-Adrenergic receptor pathways in the failing human heart. Heart Failure 1989;77-90.
Movsesian M. Cyclic AMP-mediated signal transduction in heart failure: Molecular pathophysiology and therapeutic implications. J Invest Med 1997;45:432-440.
de Tombe PP. Altered contractile function in heart failure. Cardiovasc Res 1998;37:367-80.
Arai M, Alpert NR, MacLennan DH, Parton P, Periasamy P. Alterations in sarcoplasmic reticulum gene expression in human heart failure. Circ Res 1993;72:463-469.
Rabelink TJ, Stroes ESG, Bouter KP, Morrison P. Endothelin blockers and renal protection: A new strategy to prevent end-organ damage in cardiovascular disease? Cardiovasc Res 1998;39:543-549.
Urata H, Healey B, Stewart RW, Bumpus M, Husain A. Antiotensin II-forming pathways in normal and failing human hearts. Circ Res 1990;66:883-990.
Tsuchimochi H, Kurimoto F, Ieki K, Koyama H, Fakaku F, Kawana M, Kimata S, Yazaki Y. Atrial natriuretic peptide distribution in fetal and failing adult human hearts. Circulation 1988;78:920-927.
Chidsey CA, Sonnenblick EH, Morrow AG, Braunwald E. Norepinephrine stores and contractile force of papillary muscle from the failing human heart. Circulation 1966;33:43-51.
Bristow MR, Minobe W, Rasmussen R, Larrabee P, Skerl L, Klein JW, Anderson FL, Murray J, Mestroni L, Karwande SV, Fowler M, Ginsburg R. β-Adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J Clin Invest 1992;89:803-815.
Mann DL. Mechanisms and models of heart failure. A combinatorial approach. Circulation 1999;100:999-1008.
Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeier TJ, Quaife RA, Roden RL, Dutcher DL, Robertson AD, Voelkel NF, Badesch BD, Groves BM, Gilbert EM. Changes in gene expression in the intact human heart. J Clin Invest 1997;100:2315-2324.
Anversa PL, Kajstura J, Guerra S, Beltrami CA. Myocyte death and growth in the failing heart. Lab Invest 1998;78:767-786.
Schaper J, Elsässer A, Kostin S. The role of cell death in heart failure. Circ Res 1999;85:867-869.
Hatt PY, Berjal G, Moravec J, Swynghedauw B. Heart failure: An electron microscopic study of the left ventricular papillary muscle in aortic insuffciency in the rabbit. J Mol Cell Cardiol 1970;1:235-247.
Ferrans VJ, Roberts WC. Intermyofibrillar and nuclear fibrillar connections in human and canine myocardium. An ultrastuctural study. J Mol Cell Cardiol 1973;5:247-257.
Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, Friedl A, Bleese N. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 1991;83:504-514.
Kostin S, Heling A, Hein S, Scholz D, Klövekorn W-P, Schaper J. The protein composition of the normal and diseased cardiac myocyte. Heart Fail Rev 1998;2:245-260.
Heling A, Zimmermann R, Kostin S, Maeno Y., Hein S, Devaux B, Bauer E, Klövekorn W-P, Schlepper M, Schaper W, Schaper J. Increased expression of cytoskeletal, linkage and extracellular proteins in failing human myocardium. Circ Res 2000;86:846-853.
Hein S, Kostin S, Heling A, Maeno Y, Schaper J. The role of the cytoskeleton in heart failure. Cardiovasc Res 2000; 45:273-278.
Fuchs E, Cleveland DW. A structural scaffolding of intermediate filaments in health and disease. Science 1998;279:514-519.
Choquet D, Felsenfeld DP, Sheetz MP. Extracellular-matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 1997;88:39-48.
Wang N, D.E. I. Control of cytoskeletal mechanics by extracellular matrix, cell shape and mechanical tension. Biophys J 1994;66:2181-2189.
Palmer BM, Valent S, Holder EL, Weinberger HD. Microtubules modulate cardiomyocyte β-adrenergic response in cardiac hypertrophy. Am J Physiol 1998;44:H 1707-H1716.
Liao G, Gundersen GG. Kinesin is a candidate for cross-bridging microtubules and intermediate filaments. Selective binding of detyrosinated tubulin and vimentin. J Biol Chem 1998;273:9797-9803.
Nasmyth K, Jansen RP. The cytoskeleton in mRNA loclization and cell differentiation. Curr Opinion Cell Biol 1997;9:396-400.
Pfaff, Liu S, Erle DJ, Ginsberg MH. Integrin b cytoplasmic domains differentially bind to cytoskeletal proteins. J Biol Chem 1998;273:6104-6109.
Samuel JL, Corda S, Chassagne C, Rappaport L. The extracellular matrix and the cytoskeleton in heart hypertrophy and failure. Heart Fail Rev 2000;5:239-250.
Stevenson S, Rothery S, Cullen MJ, Severs NJ. Dystrophin is not a specific component of the cardiac costamere. Circ Res 1997;80:269-280.
Kostin S, Scholz D, Shimada T, Maeno Y, Mollnau H, Hein S, Schaper J. The internal and external protein scaffold of the T-tubular system in cardiomyocytes. Cell Tissue Res 1998;294:449-460.
Klietsch L, Ervasti J, Arnold W, Campbell K, Jorgensen A. Dystrophin-glycoprotein complex and laminin colocalize to the sarcolemma and the transverse tubules of cardiac muscle. Circ Res 1993;72:349-360.
Kaprelian RR, Severs NJ. Dystrophin and the cardiomyocyte membrane cytoskeleton in the healthy and failing heart. Heart Fail Rev 2000;5:221-238.
Hall A. Rho GTPases and the actin cytoskeleton. Science 1998;279:509-514.
Koch P, Franke W. Desmosomal cadherins: Another growing multigene family of adhesion molecules. Curr Opin Cell Biol 1994;6:682-687.
Weitzer G, Milner DJ, Kim JU, Bradley A, Capetanaki Y. Cytoskeletal control of myogenesis: A desmin null mutation blocks the myogenic pathway during embryonic stem cell differentiation. Developm Biol 1996;172:422-439.
Rothen-Rutishauser BM, Ehler E, Perriard E, Messerli JM, Perriard J-C. Different behaviour of the non-sarcomeric cytoskeleton in neonatal and adult cardiomyocytes. J Mol Cell Cardiol 1998;30:19-31.
Scholz D, Diener W, Schaper J. Altered nucleus/cytoplasm relationship and degenerative structural changes in human dilated cardiomyopathy. Cardioscience 1994;5:127-138.
Hein S, Scholz D, Fujitani N, Rennollet H, Brand T, Friedl A, Schaper J. Altered expression of titin and contractile proteins in failing human myocardium. J Mol Cell Cardiol 1994;26:1291-1306.
Wang X, Li F, Campbell SE, Gerdes M. Chronic pressure overload hypertrophy and failure in guinea pigs: II. Cytoskeletal remodeling. J Mol Cell Cardiol 1999;31:319-331.
Labeit S, Kolmerer B. Titins: Giant proteins in charge of muscle ultrastructure and elasticity. Science 1995;270:293-296.
Labeit S, Kolmerer B, Linke WA. The giant protein titin. Emerging roles in physiology and pathophysiology [see comments]. Circ Res 1997;80:290-294.
Person V, Kostin S, Suzuki K, Schaper J. Antisense experiments elucidate the essential role of titin in sarcomerogenesis. Circulation 1999;100(Suppl I): 1401 (abstr).
Obermann WMJ, Gautel M, Steiner F, van der Veen PFM, Weber K, Furst DO. The structure of the sarcomeric M-band: Localization of defined domains of myomesin, M-protein, and the 250-kD carboxyterminal region of titin by immunoelectron microscopy. J Cell Biol 1996;134:1441-1453.
Obermann WMJ, Gautel M, Weber K, Fürst DO. Molecular-structure of the sarcomeric M-band-mapping of titin and myosin binding domains in myomesin and the identification of a potential regulatory phosphorylation site in myomesin. EMBO Journal 1997;16:211-220.
Sorimachi H, Freiburg A, Kolmerer B, Ishiura S, Stier G, Gregorio CC, Labeit D, Linke WA, Suzuki K, Labeit S. Tissue-specific expression and α-actinin binding properties of the Z-disc titin: Implications for the nature of the vertebrate Z-discs. J Mol Biol 1997;270:688-695.
Helmes M, Trombitas K, Granzier H. Titin develops restoring force in rat cardiac myocytes. Circ Res 1996;79:619-626.
Rappaport L, Samuel JL. Microtubules in cardiac myocytes. Int Rev Cytol 1988;113:101-143.
Tagawa H, Koide M, Sato H, Zile MR, Carabello BA, Cooper G. Cytoskeletal role in the transition from compensated to decompensated hypertrophy during adult canine left ventricular pressure overloading. Circ Res 1998;82:751-761.
Tsutsui H, Tagawa H, Kent RL, Mc Collam PL, Ishihara K, Nagatsu M, Cooper G. Role of microtubules in contractile dysfunction of hypertrophied cardiocytes. Circulation 1994;90:533-555.
Tagawa H, Koide M, Sato I, Cooper G. Cytoskeletal role in the contractile dysfunction of cardiocytes from hypertrophied and failing right ventricular myocardium. Proc Assoc Am Physicians 1996;108:218-229.
Cooper IV G. Cardiocyte cytoskeleton in hypertrophied myocardium. Heart Fail Rev 2000;5:187-202.
ter Keurs HEDJ. Microtubules in cardiac hypertrophy. Circ Res 1998;82:828-831.
Walsh R. Microtubules and pressure-overload hypertrophy. Circ Res 1997;80:295-296.
Eble DM, Spinale FG. Contractile and cytoskeletal content, structure and mRNA levels with tachycardia-induced cardiomyopathy. Am J Physiol 1995;37:H2426-H2439.
Takahashi M, Tsutsui H, Kinugawa S, Igarashisaito K, Yamamoto S, Yamamoto M, Tagawa H, Imanakayoshida K, Egashira K, Takeshita A. Role of microtubules in the contractile dysfunction of myocytes from tachycardia-induced dilated cardiomyopathy. J Mol Cell Cardiol 1998;30:1047-1057.
Collins JF, Pawloski-Dahm C, Davies MG, Ball N, Dorn GW, Walsh RA. The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. J Mol Cell Cardiol 1996;28:1435-1443.
Bailey BA, Dipla K, Li S, Houser SR. Cellular basis of contractile derangements of hypertrophied ventricular myocytes. J Mol Cell Cardiol 1997;29:1823-1835.
Granzier HL, Irving TC. Passive tension in cardiac muscle: Contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J 1995;68:1027-1044.
Capetanaki A, Milner DJ, Weitzer G. Desmin in muscle formation and maintenance: Knockouts and consequences. Cell Struct Funct 1997;22:103-116.
Thornell LE, Carlsson L, Li Z, Mericskay M, Paulin D. Null mutation in the desmin gene gives rise to cardiomyopathy. J Mol Cell Cardiol 1997;29:2107-2124.
Milner DJ, Weitzer G, Tran D, Bradley A, Capetanaki Y. Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J Cell Biol 1996;134:1255-1270.
Capetanaki Y. Desmin cytoskeleton in healthy and failing heart. Heart Fail Rev 2000;5:203-220.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kostin, S., Hein, S., Arnon, E. et al. The Cytoskeleton and Related Proteins in the Human Failing Heart. Heart Fail Rev 5, 271–280 (2000). https://doi.org/10.1023/A:1009813621103
Issue Date:
DOI: https://doi.org/10.1023/A:1009813621103