Skip to main content

Advertisement

SpringerLink
Log in

Agonist-like autoantibodies against calcium channel in patients with dilated cardiomyopathy

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

The calcium channel may be an important target in the autoimmune pathogenesis of dilated cardiomyopathy (DCM). The presence and function of serum autoantibodies against calcium channels (CC-AAbs) in patients with DCM were studied. Calcium-channel AAbs were detected in 80 patients with DCM and 80 controls by enzyme-linked immunosorbent assay (ELISA). Calcium-channel AAbs were further purified by affinity chromatography for characterization by immunoblotting and immunofluorescence. Voltage-clamp experiments were performed to identify the function of CC-AAbs. The presence of CC-AAbs was shown effectively by ELISA, and CC-AAbs were able specifically to bind to the calcium channel on the myocyte, confirmed by immunoblotting and immunofluorescence. Calcium currents were enhanced by CC-AAbs on Xenopus oocytes expressing human CaV1.2 channels, which suggested CC-AAbs in patients with DCM were agonist-like. Our results suggest there are novel agonist-like CC-AAbs in patients with DCM. Calcium-channel AAbs might play an important role in the pathogenesis of DCM.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK (2000) Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342:1077–1084

    Article  PubMed  CAS  Google Scholar 

  2. Bienertová-Vasků JA, Spinarová L, Bienert P, Vasků A (2009) Association between variants in the genes for leptin, leptin receptor, and proopiomelanocortin with chronic heart failure in the Czech population. Heart Vessels 24:131–137

    Article  PubMed  Google Scholar 

  3. Otsuka K, Terasaki F, Shimomura H, Tsukada B, Horii T, Isomura T, Suma H, Shibayama Y, Kitaura Y (2010) Enhanced expression of the ubiquitin-proteasome system in the myocardium from patients with dilated cardiomyopathy referred for left ventriculoplasty: an immunohistochemical study with special reference to oxidative stress. Heart Vessels 25:474–484

    Article  PubMed  Google Scholar 

  4. Kurt IH, Yavuzer K, Batur MK (2010) Short-term effect of levosimendan on free light chain kappa and lambda levels in patients with decompensated chronic heart failure. Heart Vessels 25:392–399

    Article  PubMed  Google Scholar 

  5. MacLellan WR, Lusis AJ (2003) Dilated cardiomyopathy: learning to live with yourself. Nat Med 9:1455–1456

    Article  PubMed  CAS  Google Scholar 

  6. Liao YH, Fu M (2001) Autoimmunity in the pathogenesis of cardiomyopathy. J Autoimmun 16:1–2

    Article  PubMed  CAS  Google Scholar 

  7. Mobini R, Staudt A, Felix SB, Baumann G, Wallukat G, Deinum J, Svensson H, Hjalmarson A, Fu M (2003) Hemodynamic improvement and removal of autoantibodies against beta1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy. J Autoimmun 20:345–350

    Article  PubMed  CAS  Google Scholar 

  8. Yoshikawa T, Baba A, Nagatomo Y (2009) Autoimmune mechanisms underlying dilated cardiomyopathy. Circ J 73:602–607

    Article  PubMed  CAS  Google Scholar 

  9. Okazaki T, Honjo T (2005) Pathogenic roles of cardiac autoantibodies in dilated cardiomyopathy. Trends Mol Med 11:322–326

    Article  PubMed  CAS  Google Scholar 

  10. Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, Honjo T (2003) Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 9:1477–1483

    Article  PubMed  CAS  Google Scholar 

  11. Schultheiss HP, Kühl U, Janda I, Melzner B, Ulrich G, Morad M (1988) Antibody-mediated enhancement of calcium permeability in cardiac myocytes. J Exp Med 168:2105–2119

    Article  PubMed  CAS  Google Scholar 

  12. Liao Y, Tu Y, Chen L, Dai S, Peng Y, Li S, Zhang J (1996) Cardiac cytotoxic mechanism mediated by antibodies against myocardial mitochondrial ADP/ATP carrier in patients with dilated cardiomyopathy. Chin Med J (Engl) 109:193–196

    CAS  Google Scholar 

  13. Liao YH, Cheng LX, Dai SP, Tu YS (1996) Autoantibodies against ADP/ATP carrier from patients with dilated cardiomyopathy increase activity of voltage-dependent Ca channels in isolated cardiac myocytes. Blood Press Suppl 3:41–44

    PubMed  CAS  Google Scholar 

  14. Liao YH (1996) Functional analysis of autoantibodies against ADP/ATP carrier from dilated cardiomyopathy. Int J Cardiol 54:165–169

    Article  PubMed  CAS  Google Scholar 

  15. Schulze K, Heineman FW, Schultheiss HP, Balaban RS (1999) Impairment of myocardial calcium homeostasis by antibodies against the adenine nucleotide translocator. Cell Calcium 25:361–370

    Google Scholar 

  16. Dong R, Liu P, Wee L, Butany J, Sole MJ (1992) Verapamil ameliorates the clinical and pathological course of murine myocarditis. J Clin Invest 90:2022–2030

    Article  PubMed  CAS  Google Scholar 

  17. Liao YH (1998) Interventional study of diltiazem in dilated cardiomyopathy: a report of multiple centre clinical trial in China. Chinese Cooperative Group of Diltiazem Intervention Trial in Dilated Cardiomyopathy. Int J Cardiol 64:25–30

    Article  PubMed  CAS  Google Scholar 

  18. Figulla HR, Gietzen F, Zeymer U, Raiber M, Hegselmann J, Soballa R, Hilgers R (1996) Diltiazem improves cardiac function and exercise capacity in patients with idiopathic dilated cardiomyopathy. Results of the Diltiazem in Dilated Cardiomyopathy Trial. Circulation 94:346–352

    Article  PubMed  CAS  Google Scholar 

  19. Nishiyama M, Park IS, Yoshikawa T, Hatai Y, Ando M, Takahashi Y, Mori K, Murakami Y (2009) Efficacy and safety of carvedilol for heart failure in children and patients with congenital heart disease. Heart Vessels 24:187–192

    Article  PubMed  Google Scholar 

  20. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P (1996) Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 93:841–842

    Article  PubMed  CAS  Google Scholar 

  21. Catterall WA, Striessnig J, Snutch TP, Perez-Reyes E et al (2003) International Union of Pharmacology. International Union of Pharmacology. XL. Compendium of voltage-gated ion channels: calcium channels. Pharmacol Rev 55:579–581

    Article  PubMed  CAS  Google Scholar 

  22. Merrifield RB (1969) Solid-phase peptide synthesis. Adv Enzymol Relat Areas Mol Biol 32:221–296

    PubMed  CAS  Google Scholar 

  23. Zhou Z, Liao YH, Wei Y, Wei F, Wang B, Li L, Wang M, Liu K (2005) Cardiac remodeling after long-term stimulation by antibodies against the alpha1-adrenergic receptor in rats. Clin Immunol 114:164–173

    Article  PubMed  CAS  Google Scholar 

  24. Li H, Zhang H, Hancox JC, Kozlowski RZ (2007) An outwardly rectifying anionic background current in atrial myocytes from the human heart. Biochem Biophys Res Commun 359:765–770

    Article  PubMed  CAS  Google Scholar 

  25. Liao YH, Yuan J, Wang ZH, Cheng X, Zhang JH, Tian Y, Dong JH, Guo HP, Wang M (2005) Infectious tolerance to ADP/ATP carrier peptides induced by anti-L3T4 monoclonal antibody in dilated cardiomyopathy mice. J Clin Immunol 25:376–384

    Article  PubMed  CAS  Google Scholar 

  26. Lei M, Jones SA, Liu J, Lancaster MK, Fung SS, Dobrzynski H, Camelliti P, Maier SK, Noble D, Boyett MR (2004) Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking. J Physiol 559:835–848

    PubMed  CAS  Google Scholar 

  27. Wang X, Liao Y, Zou A, Li L, Tu D (2007) Blockade action of ketanserin and increasing effect of potassium ion on Kv1.3 channels expressed in Xenopus oocytes. Pharmacol Res 56:148–154

    Article  PubMed  CAS  Google Scholar 

  28. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT (2005) Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA 102:8089–8096

    Article  PubMed  CAS  Google Scholar 

  29. Reichlin M (1998) Cellular dysfunction induced by penetration of autoantibodies into living cells: cellular damage and dysfunction mediated by antibodies to dsDNA and ribosomal P proteins. J Autoimmun 11:557–561

    Article  PubMed  CAS  Google Scholar 

  30. Bourinet E, Mangoni ME, Nargeot J (2004) Dissecting the functional role of different isoforms of the L-type Ca2+ channel. J Clin Invest 113:1382–1384

    PubMed  CAS  Google Scholar 

  31. Sun F, Hayama E, Katsube Y, Matsuoka R, Nakanishi T (2010) The role of the large-conductance voltage-dependent and calcium-activated potassium (BK(Ca)) channels in the regulation of rat ductus arteriosus tone. Heart Vessels 25:556–564

    Article  PubMed  Google Scholar 

  32. Takahashi A, Shiga T, Shoda M, Tanizaki K, Manaka T, Ejima K, Kasanuki H, Hagiwara N (2010) Gender difference in arrhythmic occurrences in patients with nonischemic dilated cardiomyopathy and implantable cardioverter-defibrillator. Heart Vessels 25:150–154

    Article  PubMed  Google Scholar 

  33. Jane-wit D, Altuntas CZ, Johnson JM, Yong S, Wickley PJ, Clark P, Wang Q, Popović ZB, Penn MS, Damron DS, Perez DM, Tuohy VK (2007) Beta 1-adrenergic receptor autoantibodies mediate dilated cardiomyopathy by agonistically inducing cardiomyocyte apoptosis. Circulation 116:399–410

    Article  PubMed  CAS  Google Scholar 

  34. Jahns R, Boivin V, Hein L, Triebel S, Angermann CE, Ertl G, Lohse MJ (2004) Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest 113:1419–1429

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Basic Research Program of China (973 Program: 2007CB512000; 2007CB512005) to Y.-H.L. We thank Michael C. Sanguinetti for the CaV1.2, CaVβ2b, and CaVα2δ1 cDNA.

Author information

Authors and Affiliations

  1. Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie-Fang Avenue, 430022, Wuhan, Hubei, China

    Hua Xiao, Min Wang, Jing Yuan, Guanghong Zhao & Yu-Hua Liao

  2. Research Center of Ion Channelopathy, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Hua Xiao, Yimei Du & Danna Tu

Authors
  1. Hua Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yimei Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guanghong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Danna Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-Hua Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu-Hua Liao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xiao, H., Wang, M., Du, Y. et al. Agonist-like autoantibodies against calcium channel in patients with dilated cardiomyopathy. Heart Vessels 27, 486–492 (2012). https://doi.org/10.1007/s00380-011-0176-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-011-0176-7

Keywords

Search

Navigation