Skip to main content
Log in

Modulation of sarcoplasmic reticulum Ca2+ cycling in systolic and diastolic heart failure associated with aging

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Hypertension, atherosclerosis, and resultant chronic heart failure (HF) reach epidemic proportions among older persons, and the clinical manifestations and the prognoses of these worsen with increasing age. Thus, age per se is the major risk factor for cardiovascular disease. Changes in cardiac cell phenotype that occur with normal aging, as well as in HF associated with aging, include deficits in ß-adrenergic receptor (ß-AR) signaling, increased generation of reactive oxygen species (ROS), and altered excitation–contraction (EC) coupling that involves prolongation of the action potential (AP), intracellular Ca2+ (Ca 2+i ) transient and contraction, and blunted force- and relaxation-frequency responses. Evidence suggests that altered sarcoplasmic reticulum (SR) Ca2+ uptake, storage, and release play central role in these changes, which also involve sarcolemmal L-type Ca2+ channel (LCC), Na+–Ca2+ exchanger (NCX), and K+ channels. We review the age-associated changes in the expression and function of Ca2+ transporting proteins, and functional consequences of these changes at the cardiac myocyte and organ levels. We also review sexual dimorphism and self-renewal of the heart in the context of cardiac aging and HF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, Napoli C, Rengo F (1996) The role of aging on the control of contractile force by Na+–Ca2+ exchange in rat papillary muscle. J Gerontol A Biol Sci Med Sci 51:M251–M259

    CAS  PubMed  Google Scholar 

  2. Anversa P, Palackal T, Sonnenblick EH, Olivetti G, Meggs LG, Capasso JM (1990) Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res 67:871–885

    CAS  PubMed  Google Scholar 

  3. Anversa P, Rota M, Urbanek K, Hosoda T, Sonnenblick EH, Leri A, Kajstura J, Bolli R (2005) Myocardial aging-a stem cell problem. Basic Res Cardiol 100:482–493

    Article  CAS  PubMed  Google Scholar 

  4. Armand A-S, De Windt LJ (2004) Calcium cycling in heart failure: how the fast became too furious. Cardiovasc Res 62:439–441

    Article  CAS  PubMed  Google Scholar 

  5. Assayag P, Charlemagne D, Marty I, de Leiris J, Lompre AM, Boucher F, Valere PE, Lortet S, Swynghedauw B, Besse S (1998) Effects of sustained low-flow ischemia on myocardial function and calcium-regulating proteins in adult and senescent rat hearts. Cardiovasc Res 38:169–180

    Article  CAS  PubMed  Google Scholar 

  6. Bassani RA (2006) Transient outward potassium current and Ca2+ homeostasis in the heart: beyond the action potential. Braz J Med Biol Res 39:393–403

    Article  CAS  PubMed  Google Scholar 

  7. Bito V, Heinzel FR, Biesmans L, Antoons G, Sipido KR (2008) Crosstalk between L-type Ca2+ channels and the sarcoplasmic reticulum: alterations during cardiac remodeling. Cardiovasc Res 77:315–324

    Article  CAS  PubMed  Google Scholar 

  8. Boheler KR, Volkova M, Morrell C, Garg R, Zhu Y, Marguelis K, Seymour AM, Lakatta EG (2003) Sex- and age-dependent human transcriptome variability: implications for chronic heart failure. Proc Natl Acad Sci USA 100:2754–2759

    Article  CAS  PubMed  Google Scholar 

  9. Boluyt MO, Lakatta EG (1998) Cardiovascular aging in health. In: Altschuld RA, Haworth RA (eds) Heart metabolism in failure, vol 4B. Connecticut JAI Press Inc, Greenwich, pp 257–303

    Chapter  Google Scholar 

  10. Brenner DA, Apstein CS, Saupe KW (2001) Exercise training attenuates age-associated diastolic dysfunction in rats. Circulation 104:221–226

    CAS  PubMed  Google Scholar 

  11. Caffrey JL, Boluyt MO, Younes A, Barron BA, O’Neill L, Crow MT, Lakatta EG (1994) Aging, cardiac proenkephalin mRNA and enkephalin peptides in the Fisher 344 rat. J Mol Cell Cardiol 26:701–711

    Article  CAS  PubMed  Google Scholar 

  12. Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, Colussi C, Di Meglio F, Nadal-Ginard B, Frustaci A, Leri A, Maseri A, Anversa P (2003) Senescence and death of primitive cells and myocytes leads to premature cardiac aging and heart failure. Circ Res 93:604–613

    Article  CAS  PubMed  Google Scholar 

  13. Cigola E, Kastura J, Li B, Meggs LG, Anversa P (1997) Angiotensin II activates programmed myocyte cell death in vitro. Exp Cell Res 231:363–371

    Article  CAS  PubMed  Google Scholar 

  14. del Monte F, Harding SE, Dec GW, Gwathmey JK, Hajjar RJ (2002) Targeting phospholamban by gene transfer in human heart failure. Circulation 105:904–907

    Article  CAS  PubMed  Google Scholar 

  15. Dibb K, Rueckschloss U, Eisner D, Insberg G, Trafford A (2004) Mechanisms underlying enhanced excitation contraction coupling observed in the senescent sheep myocardium. J Mol Cell Cardiol 37:1171–1181

    CAS  PubMed  Google Scholar 

  16. Fermin DR, Barac A, Lee S, Polster SP, Hannenhalli S, Bergemann TL, Grindle S, Dyke DB, Pagani F, Miller LW, Tan S, dos Remedios C, Cappola TP, Margulies KB, Hall JL (2008) Sex and age dimorphism of myocardial gene expression in nonischemic human heart failure. Circulation 1:117–125

    CAS  PubMed  Google Scholar 

  17. Fraticelli A, Josephson R, Danziger R, Lakatta E, Spurgeon H (1989) Morphological and contractile characteristics of rat cardiac myocytes from maturation to senescence. Am J Physiol 257:H259–H265

    CAS  PubMed  Google Scholar 

  18. Froehlich JP, Lakatta EG, Beard E, Spurgeon HA, Weisfeldt ML, Gerstenblith G (1978) Studies of sarcoplasmic reticulum function and contraction duration in young and aged rat myocardium. J Mol Cell Cardiol 10:427–438

    Article  CAS  PubMed  Google Scholar 

  19. Frolkis VV, Frolkis RA, Mkhitarian LS, Shevchuk VG, Fraifeld VE, Vakulenko LG, Syrovy I (1988) Contractile function and Ca2+ transport system of myocardium in ageing. Gerontology 34:64–74

    Article  CAS  PubMed  Google Scholar 

  20. Gonzalez A, Rota M, Nurzynska D, Misao Y, Tillmanns J, Ojaimi C, Padin-Iruegas ME, Müller P, Esposito G, Bearzi C, Vitale S, Dawn B, Anganalmath SK, Baker M, Hintze TH, Bolli R, Urbanek K, Hosoda T, Anversa P, Kajstura J, Leri A (2008) Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res 102:597–606

    Article  CAS  PubMed  Google Scholar 

  21. Grandy SA, Howlett SE (2006) Cardiac excitation-contraction coupling is altered in myocytes from aged male mice but not in cells from aged female mice. Am J Physiol 291:H2362–H2370

    CAS  Google Scholar 

  22. Guo T, Zhang T, Mestril R, Bers DM (2006) Ca/calmodulin-dependent protein kinase II phosphorylation of ryanodine receptor does affect calcium sparks in mouse ventricular myocytes. Circ Res 99:398–406

    Article  CAS  PubMed  Google Scholar 

  23. Hano O, Bogdanov KY, Sakai M, Danziger RG, Spurgeon HA, Lakatta EG (1995) Reduced threshold for myocardial cell calcium intolerance in the rat heart with aging. Am J Physiol 269:H1607–H1612

    CAS  PubMed  Google Scholar 

  24. Helenius M, Hänninen M, Lehtinen SK, Salminen A (1996) Aging-induced up-regulation of nuclear binding activities of oxidative stress responsive NF-β transcription factor in mouse cardiac muscle. J Mol Cell Cardiol 28:487–498

    Article  CAS  PubMed  Google Scholar 

  25. Heyliger C, Prakash A, McNeill J (1988) Alterations in membrane Na+–Ca2+ exchange in the aging myocardium. Age 1988:1–6

    Article  Google Scholar 

  26. Howlett SE, Grandy SA, Ferrier GR (2006) Calcium spark properties in ventricular myocytes are altered in aged mice. Am J Physiol 290:H1566–H1574

    CAS  Google Scholar 

  27. Isenberg G, Borschke B, Rueckschloss U (2003) Ca2+ transients in cardiomyocytes from senescent mice peak late and decay slowly. Cell Calcium 34:271–280

    Article  CAS  PubMed  Google Scholar 

  28. Janapati V, Wu A, Davis N, Derrico CA, Levengood J, Schummers J, Colvin RA (1995) Post-transcriptional regulation of the Na+/Ca2+ exchanger in aging rat heart. Mech Ageing Dev 84:195–208

    Article  CAS  PubMed  Google Scholar 

  29. Janczewski AM, Spurgeon HA, Lakatta EG (2002) Action potential prolongation in cardiac myocytes of old rats is an adaptation to sustain youthful intracellular Ca2+ regulation. J Mol Cell Cardiol 34:641–648

    Article  CAS  PubMed  Google Scholar 

  30. Janczewski AM, Kadokami T, Lemster B, Frye CS, McTiernan CF, Feldman AM (2003) Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-α. Am J Physiol 284:H960–H969

    CAS  Google Scholar 

  31. Jiang MT, Moffat MP, Narayanan N (1993) Age-related alterations in the phosphorylation of sarcoplasmic reticulum and myofibrillar proteins and diminished contractile response to isoproterenol in intact rat ventricle. Circ Res 72:102–111

    CAS  PubMed  Google Scholar 

  32. Josephson IR, Guia A, Stern MD, Lakatta EG (2002) Alterations in properties of L-type Ca channels in aging rat heart. J Mol Cell Cardiol 34:297–308

    Article  CAS  PubMed  Google Scholar 

  33. Kadokami T, McTiernan CF, Kubota T, Frye CS, Feldman AM (2000) Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J Clin Invest 106:589–597

    Article  CAS  PubMed  Google Scholar 

  34. Kajstura J, Urbanek K, Rota M, Bearzi C, Hosoda T, Bolli R, Anversa P, Leri A (2008) Cardiac stem cells and myocardial disease. J Mol Cell Cardiol 45:505–513

    Article  CAS  PubMed  Google Scholar 

  35. Kaplan P, Jurkovicova D, Babusikova E, Hudecova S, Racay P, Sirova M, Lehotsky J, Drgova A, Dobrota D, Krizanova O (2007) Effect of aging on the expression of intracellular Ca2+ transport proteins in a rat heart. Mol Cell Biochem 301:219–226

    Article  CAS  PubMed  Google Scholar 

  36. Konhilas JP, Leinwand LA (2007) The effects of biological sex and diet on the development of heart failure. Circulation 116:2747–2759

    Article  PubMed  Google Scholar 

  37. Lakatta EG (1992) Functional implications of spontaneous sarcoplasmic reticulum Ca2+ release in the heart. Cardiovasc Res 26:193–214

    Article  CAS  PubMed  Google Scholar 

  38. Lakatta EG (1993) Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 73:413–465

    CAS  PubMed  Google Scholar 

  39. Lakatta EG (1999) Cardiovascular aging research: the next horizons. J Am Geriatr Soc 47:613–625

    CAS  PubMed  Google Scholar 

  40. Lakatta EG, Sollott SJ, Pepe S (2001) The old heart: operating on the edge. In: Ageing vulnerability: causes and interventions. Novartis foundation symposium 235. Wiley, Ltd, pp 172–201

  41. Leinwand LA (2003) Sex is a potent modifier of the cardiovascular system. J Clin Invest 112:302–307

    CAS  PubMed  Google Scholar 

  42. Leri A, Malhotra A, Liew CC, Kajstura J, Anversa P (2000) Telomerase activity in rat cardiac myocytes is age and gender dependent. J Mol Cell Cardiol 32:385–390

    Article  CAS  PubMed  Google Scholar 

  43. Li Y, Kranias EG, Mignery GA, Bers DM (2002) Protein kinase a phosphorylation of the ryanodine receptor does not affect calcium sparks in mouse ventricular myocytes. Circ Res 90:309–316

    Article  CAS  PubMed  Google Scholar 

  44. Li Q, Wu S, Li S-Y, Lopez FL, Du M, Kajstura J, Anversa P, Ren J (2007) Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage. Am J Physiol 292:H1398–H1403

    Article  CAS  Google Scholar 

  45. Lim CC, Apstein CS, Colucci WS, Liao R (2000) Impaired cell shortening and relengthening with increased pacing frequency are intrinsic to the senescent mouse cardiomyocyte. J Mol Cell Cardiol 32:2075–2082

    Article  CAS  PubMed  Google Scholar 

  46. Lim CC, Liao R, Varma N, Apstein CS (1999) Impaired lusitropy-frequency in the aging mouse: role of Ca2+ handling proteins and effects of isoproterenol. Am J Physiol 277:H2083–H2090

    CAS  PubMed  Google Scholar 

  47. Liu SJ, Wyeth RP, Melchert RB, Kennedy RH (2000) Aging-associated changes in whole cell K+ and L-type Ca2+ currents in rat ventricular myocytes. Am J Physiol 279:H889–H900

    CAS  Google Scholar 

  48. Lucas D, Sweda L (1998) Cardiac reperfusion injury, aging, lipid peroxidation, and mitochondrial dysfunction. Proc Natl Acad Sci USA 95:510–514

    Article  CAS  PubMed  Google Scholar 

  49. Mace LC, Palmer BM, Brown DA, Jew KN, Lynch JM, Glunt JM, Parsons TA, Cheung JY, Moore RL (2003) Influence of age and run training on cardiac Na+/Ca2+ exchange. J Appl Physiol 95:1994–2003

    CAS  PubMed  Google Scholar 

  50. MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4:566–577

    Article  CAS  PubMed  Google Scholar 

  51. Marks AR (2000) Cardiac intracellular calcium release channels: role in heart failure. Circ Res 87:8–11

    CAS  PubMed  Google Scholar 

  52. Nitta Y, Abe K, Aoki M, Ohno I, Isoyama S (1994) Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia. Am J Physiol 267:H1795–H1803

    CAS  PubMed  Google Scholar 

  53. Olivetti G, Giordano G, Corradi D, Melissari M, Lagrasta C, Gambert SR, Anversa P (1995) Gender differences and aging: effects on the human heart. J Am Coll Cardiol 26:1068–1079

    Article  CAS  PubMed  Google Scholar 

  54. Orchard CH, Lakatta EG (1985) Intracellular calcium transients and developed tensions in rat heart muscle. A mechanism for the negative interval-strength relationship. J Gen Physiol 86:637–651

    Article  CAS  PubMed  Google Scholar 

  55. Pepe S, Tsuchiya N, Lakatta EG, Hansford RG (1999) PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. Am J Physiol 276:H149–H158

    CAS  PubMed  Google Scholar 

  56. Rota M, Hosoda T, De Angelis A, Arcarese ML, Esposito G, Rizzi R, Tillmanns J, Tugal D, Musso E, Rimoldi O, Bearzi C, Urbanek K, Anversa P, Leri A, Kajstura J (2007) The young mouse heart is composed of myocytes heterogeneous in age and function. Circ Res 101:387–399

    Article  CAS  PubMed  Google Scholar 

  57. Sakai M, Danziger RS, Staddon JM, Lakatta EG, Hansford RG (1989) Decrease with senescence in the norepinephrine-induced phosphorylation of myofilament proteins in isolated rat cardiac myocytes. J Mol Cell Cardiol 21:1327–1336

    Article  CAS  PubMed  Google Scholar 

  58. Schmidt U, del Monte F, Miyamoto MI, Matsui T, Gwathmey JK, Rosenzweig A, Hajjar RJ (2000) Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca2+-ATPase. Circulation 101:790–796

    CAS  PubMed  Google Scholar 

  59. Schmidt U, Zhu X, Lebeche D, Huq F, Guerrero JL, Hajjar RJ (2005) In vivo gene transfer of parvalbumin improves diastolic function in aged rat hearts. Cardiovasc Res 66:318–323

    Article  CAS  PubMed  Google Scholar 

  60. Shida M, Isoyama S (1993) Effects of age on c-fos and c-myc gene expression in response to hemodynamic stress in isolated, perfused rat hearts. J Mol Cell Cardiol 25:1025–1035

    Article  CAS  PubMed  Google Scholar 

  61. Shunkert H, Weinberg E, Bruckschlegel G, Riegger AJ, Lorell BH (1995) Alteration of growth responses in established cardiac pressure overload hypertrophy in rats with aortic banding. J Clin Invest 96:2768–2774

    Article  Google Scholar 

  62. Sipido KR, Eisner D (2005) Something old, something new: Changing views on the cellular mechanisms of heart failure. Cardiovasc Res 68:167–174

    Article  CAS  PubMed  Google Scholar 

  63. Slack JP, Grupp IL, Dash R, Holder D, Schmidt A, Gerst MJ, Tamura T, Tilgmann C, James PF, Johnson R, Gerdes AM, Kranias EG (2001) The enhanced contractility of the phospholamban-deficient mouse heart persists with aging. J Mol Cell Cardiol 33:1031–1040

    Article  CAS  PubMed  Google Scholar 

  64. Spurgeon HA, Steinbach MF, Lakatta EG (1983) Chronic exercise prevents characteristic age-related changes in rat cardiac contraction. Am J Physiol 244:H513–H518

    CAS  PubMed  Google Scholar 

  65. Taffet GE, Tate CA (1993) CaATPase content is lower in cardiac sarcoplasmic reticulum isolated from old rats. Am J Physiol 264:H1609–H1614

    CAS  PubMed  Google Scholar 

  66. Takahashi T, Schunkert H, Isoyama S, Wei JY, Nadal-Ginard B, Grossman W, Izumo S (1992) Age-related differences in the expression of proto-oncogene and contractile protein genes in response to pressure overload in the rat myocardium. J Clin Invest 89:939–946

    Article  CAS  PubMed  Google Scholar 

  67. Tate CA, Taffet GE, Hudson EK, Blaylock SL, McBride RP, Michael LH (1990) Enhanced calcium uptake of cardiac sarcoplasmic reticulum in exercise-trained old rats. Am J Physiol 258:H431–H435

    CAS  PubMed  Google Scholar 

  68. Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA, Urbanek K, Nadal-Ginard B, Kajstura J, Anversa P, Leri A (2004) Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res 94:514–524

    Article  CAS  PubMed  Google Scholar 

  69. Van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callendere M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Lüscher TF (2000) Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 192:1731–1743

    Article  PubMed  Google Scholar 

  70. Wahr PA, Michele DE, Metzger JM (2000) Effects of aging on single cardiac myocyte function in Fischer 344 x Brown Norway rats. Am J Physiol 279:H559–H565

    CAS  Google Scholar 

  71. Walker KE, Lakatta EG, Houser SR (1993) Age associated changes in membrane currents in rat ventricular myocytes. Cardiovasc Res 27:1968–1977

    Article  CAS  PubMed  Google Scholar 

  72. Wei JY, Spurgeon A, Lakatta EG (1984) Excitation-contraction in rat myocardium: alterations with adult aging. Am J Physiol 246:H784–H791

    CAS  PubMed  Google Scholar 

  73. Xiao RP, Spurgeon HA, O’Connor F, Lakatta EG (1994) Age-associated changes in beta-adrenergic modulation on rat cardiac excitation-contraction coupling. J Clin Invest 94:2051–2059

    Article  CAS  PubMed  Google Scholar 

  74. Xiao R-P, Tomhave ED, Wang DJ, Ji X, Boluyt MO, Cheng H, Lakatta EG, Koch WJ (1998) Age-associated reductions in cardiac ß1 - and ß2 -adrenoceptor responses without changes in inhibitory G proteins or receptor kinases. J Clin Invest 101:1273–1282

    Article  CAS  PubMed  Google Scholar 

  75. Xu A, Hawkins C, Narayanan N (1993) Phosphorylation and activation of the Ca2+-ATPase of cardiac sarcoplasmic reticulum by Ca2+/calmodulin-dependent protein kinase. J Biol Chem 268:8394–8397

    CAS  PubMed  Google Scholar 

  76. Xu A, Narayanan N (1998) Effects of aging on sarcoplasmic reticulum Ca2+-cycling proteins and their phosphorylation in rat myocardium. Am J Physiol 275:H2087–H2094

    CAS  PubMed  Google Scholar 

  77. Yin FC, Spurgeon HA, Weisfeldt ML, Lakatta EG (1980) Mechanical properties of myocardium from hypertrophied rat hearts. A comparison between hypertrophy induced by senescence and by aortic banding. Circ Res 46:292–300

    CAS  PubMed  Google Scholar 

  78. Younes A, Boluyt MO, O’Neill L, Meredith AL, Crow MT, Lakatta EG (1995) Age-associated increase in rat ventricular ANP gene expression correlates with cardiac hypertrophy. Am J Physiol 38:H1003–H1008

    Google Scholar 

  79. Zhang SJ, Zhou YY, Xiao RP et al (2000) Age-associated reduction in recovery of the equilibrium state of myocyte length during reduced interstimulus intervals at higher stimulation rates. Biophys J 78:227A (Abstract)

    Article  Google Scholar 

  80. Zhu X, Altschafl BA, Hajjar RJ, Valdivia HH, Schmidt U (2005) Altered Ca2+ sparks and gating properties of ryanodine receptors in aging cardiomyocytes. Cell Calcium 37:583–591

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Edward G. Lakatta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Janczewski, A.M., Lakatta, E.G. Modulation of sarcoplasmic reticulum Ca2+ cycling in systolic and diastolic heart failure associated with aging. Heart Fail Rev 15, 431–445 (2010). https://doi.org/10.1007/s10741-010-9167-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-010-9167-5

Keywords

Navigation