Advertisement

Immune-mediated modulation of sarcoplasmic reticulum function in human dilated cardiomyopathy

  • C. J. Limas
  • C. Limas
Conference paper

Summary

Calcium transport by the cardiac sarcoplasmic reticulum is depressed in human dilated cardiomyopathy, but the mechanisms involved are not clear. The possible involvement of immunological mechanisms was explored by evaluating the effect of sera from 49 patients with dilated cardiomyopathy on oxalate-facilitated Ca2 + uptake. In 14 of these patients, serum or IgG induced a time- and concentration-dependent decline (29 ± 4% at 100-fold serum dilution) in Ca 2+ transport. In 14 patients, autoantibodies against the -adrenoceptor were also demonstrated by a ligand binding inhibition assay. Serum from these patients inhibited the isoproterenol-mediated stimulation of Ca2+ uptake in permeabilized cardiac myocytes, but did not prevent the effect of protein kinase A. Anti-β-receptor antibodies were present in 50% of the sera inhibiting Ca2 + uptake compared to 20% of those without inhibitory activity, (p < 0.01). There was a strong correlation between the inhibition of sarcoplasmic reticulum Ca2+ transport and the HLA-DR4 phenotype (78% compared to 30% in patients with no inhibitory effect). These results suggest that immunological mechanisms play an important role in modifying sarcoplasmic reticulum function in about a third of the patients with detailed cardiomyopathy.

Keywords

Sarcoplasmic reticulum dilated cardiomyopathy autoantibodies calcium transport HLA antigens 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Brandl CJ, Green NM, Korczak B, MacLennan DH (1986) Two Ca2 + -ATPase genes: Homologies and mechanistic implications of deduced amino acid sequences. Cell 44: 459–607CrossRefGoogle Scholar
  2. 2.
    Caforio ALP, Bonifacio E, Stewart JT, Neglia D, Parodi O, Bottazzo GF, McKenna WJ (1990) Novel organ-specific circulating cardiac autoantibodies in dilated cardiomyopathy. J Am Coll Cardiol; 15: 1527–1534PubMedCrossRefGoogle Scholar
  3. 3.
    Grossman W, McLaurin LP, Rolett EL (1979) Alterations in left ventricular relaxation and diastolic compliance in congestive cardiomyopathy. Cardiovasc Res 13: 514–522PubMedCrossRefGoogle Scholar
  4. 4.
    Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ, Feldman MD, Grossman W, Morgan JP (1987) Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res 61: 70–76PubMedGoogle Scholar
  5. 5.
    Harigaya S, Schwartz A (1969) Rate of calcium binding and uptake in normal animal and failing human cardiac muscle; membrane vesicles (relaxing system) and mitochondria. Circ Res 25: 781–794PubMedGoogle Scholar
  6. 6.
    Holmberg SRM, Williams AJ (1989) Single channel recordings from human cardiac sarcoplasmic reticulum. Circ Res 65: 1445–1449PubMedGoogle Scholar
  7. 7.
    Jorgensen AO, Arnold W, Pepper DR, Kahl SD, Mandel F, Campbell KP (1988) A monoclonal antibody to the Ca2 +-ATPase of cardiac sarcoplasmic reticulum cross-reacts with slow type I but not with fast type II canine skeletal muscle fibers: an immunocyto- chemical and immunochemical study. Cell Motil Cytoskel 9: 164–174CrossRefGoogle Scholar
  8. 8.
    Komuro I, Kurabayashi M, Shibazaki Y, Takaku F, Yazaki Y (1989) Molecular cloning and characterization of a Ca2+ + Mg2 +-dependent adenosine triphosphatase from rat cardiac sarcoplasmic reticulum. Regulation of its expression by pressure overload and developmental stage. J Clin Invest 83: 1102–1108PubMedCrossRefGoogle Scholar
  9. 9.
    Limas CJ (1978) Calcium transport ATPase of cardiac sarcoplasmic reticulum in experimental hyperthyroidism. Am J Physiol 235: H745–H751PubMedGoogle Scholar
  10. 10.
    Limas CJ, Olivari MT, Goldenberg IF, Levine TB, Benditt DG, Simon A (1987) Calcium uptake by cardiac sarcoplasmic reticulum in human dilated cardiomyopathy. Cardiovasc Res 21: 601–605PubMedCrossRefGoogle Scholar
  11. 11.
    Limas CJ, Goldenberg IF, Limas C (1989) Autoantibodies against ß-adrenoceptors in human idiopathic dilated cardiomyopathy. Circ Res 64: 97–103PubMedGoogle Scholar
  12. 12.
    Limas CJ, Limas C, Kubo SH, Olivari MT (1990) Anti-beta-receptor antibodies in human dilated cardiomyopathy and correlation with the HLA-DR antigens. Am J Cardiol 65: 483–487.PubMedCrossRefGoogle Scholar
  13. 13.
    Limas CJ, Goldenberg IF, Limas C (1990) Influence of anti-beta-receptor antibodies on cardiac adenylate cyclase in patients with idiopathic dilated cardiomyopathy. Am Heart J 119: 1322–1328PubMedCrossRefGoogle Scholar
  14. 14.
    Mercadier JJ, Lompre AM, Due P, Boheler KR, Fraysse JB, Wisnewsky C, Allen PD, Komajda M, Schwartz K (1990) Altered Sarcoplasmic reticulum Ca2+ ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest 85: 305–309PubMedCrossRefGoogle Scholar
  15. 15.
    Miyakoda G, Yoshida A, Takisawa H, Nakamure T (1987) β-Adrenergic regulation of contractility and protein phosphorylation in spontaneously beating isolated rat myocaridal cells. J Biochem (Tokyo) 102: 211–224Google Scholar
  16. 16.
    Molnar E, Seidler NW, John I, Martonosi AN (1990) The binding of monoclonal and polyclonal antibodies to the Ca2+-ATPase if sarcoplasmic reticulum: effects on interactions between ATPase molecules. Biochem Biophys Act 1023: 147–167CrossRefGoogle Scholar
  17. 17.
    Movsesian MA, Bristow MR, Krall J (1989) Ca2+ uptake by cardiac sarcoplasmic reticulum from patients with idiopathic dilated cardiomyopathy. Circ Res 65: 1141–1144.PubMedGoogle Scholar
  18. 18.
    Movsesian MA, Colyer JJ, Wang JH, Krall J (1990) Phospholamban-mediated stimulation of Ca2+ uptake in sarcoplasmic reticulum from normal and failing hearts. J Clin Invest 85: 1698–1702PubMedCrossRefGoogle Scholar
  19. 19.
    Neumann DA, Burek CL, Baughman KL, Rose NR, Herskowitz A (1990) Circulating heart-reactive antibodies in patients with myocarditis or cardimyopathy. J Am Coll Cardiol 16: 839–846PubMedCrossRefGoogle Scholar
  20. 20.
    Ogawa Y (1968) The apparent binding constant of glycoletherdiaminetetraacetic acid for calcium at neutral pH. J Biochem (Tokyo) 64: 255 - 257Google Scholar
  21. 21.
    Schulze K, Becker BF, Schauer R, Schultheiss HP (1990) Antibodies to ADP-ATP carrier- an autoantigen in myocarditis and dilated cardiomyopathy-impair cardiac function. Circulation 81: 959–969PubMedCrossRefGoogle Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co.KG, Darmstadt 1992

Authors and Affiliations

  • C. J. Limas
    • 1
    • 2
    • 3
  • C. Limas
    • 1
    • 2
  1. 1.Department of Medicine (Cardiovascular Division)and Laboratory MedicineUniversity of Minnesota School of Medicine and the Department of Veterans Affairs Medical CenterMinneapolisUSA
  2. 2.Department of PathologyUniversity of Minnesota School of Medicine and the Department of Veterans Affairs Medical CenterMinneapolisUSA
  3. 3.Cardiovascular DivisionDepartment of Medicine University of Minnesota Medical SchoolMinneapolisUSA

Personalised recommendations