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Cyclic peptide RD808 reduces myocardial injury induced by β1-adrenoreceptor autoantibodies

  • Yu Dong
  • Yan Bai
  • Shangyue Zhang
  • Wenli Xu
  • Jiahui Xu
  • Yi Zhou
  • Suli Zhang
  • Ye Wu
  • Haicun Yu
  • Ning Cao
  • Huirong LiuEmail author
  • Wen WangEmail author
Original Article
  • 41 Downloads

Abstract

Autoantibodies against the second extracellular loop of β1-adrenergic receptor (β1-AA) have been shown to be involved in the development of cardiovascular diseases. Recently, there has been considerable interest in strategies to remove these autoantibodies, particularly therapeutic peptides to neutralize β1-AA. Researchers are investigating the roles of cyclic peptides that mimic the structure of relevant epitopes on the β1-AR-ECII in a number of immune-mediated diseases. Here, we used a cyclic peptide, namely, RD808, to neutralize β1-AA, consequently alleviating β1-AA-induced myocardial injury. We investigated the protective effects of RD808 on the myocardium both in vitro and in vivo. RD808 was found to increase the survival rate of cardiomyocytes; furthermore, it decreased myocardial necrosis and apoptosis and improved the cardiac function of BalB/c mice in a β1-AA transfer model. In vitro and in vivo experiments showed that myocardial autophagy was increased in the presence of RD808, which might contribute to its cardioprotective effects. Our findings indicate that RD808 reduced myocardial injury induced by β1-AA.

Keywords

β1-Adrenergic receptor Autoantibody against the second extracellular loop of β1-adrenergic receptor Myocardial injury Cyclic peptide RD808 

Notes

Acknowledgements

We acknowledge the assistance of Mrs. Ying Yang and Mrs. Qing Xu for surface plasmon resonance (SPR) technology and Doppler ultrasound for cardiac function detection in the Core Facility Center, Capital Medical University. Fundings were provided by the Natural Science Foundation of Beijing (7151001) to Wen Wang and 973 Special Preliminary Study Plan (2014CB560704) to Huirong Liu. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

Conceived and designed the experiments: HL, WW. Performed the experiments: YD, YB, SZ, WX, JX, YZ, HY, NC. Analyzed the data: YD, YW. Contributed reagents/materials/analysis tools: SZ. Contributed to the writing of the manuscript: YD.

Conflict of interest

The authors declare the absence of any competing interest.

Supplementary material

380_2018_1321_MOESM1_ESM.tif (102 kb)
Figure S1. RD808 was purified by HPLC and MS. The purity of this peptide was > 98%. (A) HPLC result of RD808. (B) MS result of RD808 (TIF 103 kb)
380_2018_1321_MOESM2_ESM.tif (490 kb)
Figure S2. The LVEF declined at 8 weeks during β1-AA treatment. LVEF was detected in 16 weeks of β1-AA treatment mice, here ISO was used as a positive control of a classical heart failure model. Results showed that there was a significant decrease of left ventricular pump function with the existence of β1-AA at 8 weeks. These experiments have been conducted independently of the RD808-study. ISO: Isoproterenol. Data were expressed as means ± SD. *P<0.05 vs. Vehicle group, n=6 (TIF 491 kb)
380_2018_1321_MOESM3_ESM.tif (431 kb)
Figure S3. Level of LDH in supernatant of NRCMs.. Data were expressed as means ± SD. **P<0.01 vs. Vehicle group, #P<0.05 ##P<0.01 vs. β1-AA group, n=6 (TIF 432 kb)
380_2018_1321_MOESM4_ESM.tif (1.5 mb)
Figure S4. Safety assessment of RD808 in vitro. The cell survival rate and LDH release in supernatant of NRCMs were detected after challenged with different concentration of RD808 for different time. There was no significant change after RD808 administration compared to vehicle group. (A) Cell survival rate assay with CCK-8. (B) LDH in supernatant. Data were expressed as means ± SD. n=4 (TIF 1576 kb)
380_2018_1321_MOESM5_ESM.doc (44 kb)
Supplementary material 5 (DOC 44 kb)

References

  1. 1.
    Wang Y, Peng X, Nie X, Chen L, Weldon R, Zhang W, Xiao D, Cai J (2016) Burden of hypertension in China over the past decades: systematic analysis of prevalence, treatment and control of hypertension. Eur J Prev Cardiol 23:792–800CrossRefGoogle Scholar
  2. 2.
    Rollefstad S, Ikdahl E, Hisdal J, Kvien TK, Pedersen TR, Semb AG (2015) Association of chest pain and risk of cardiovascular disease with coronary atherosclerosis in patients with inflammatory joint diseases. Front Med (Lausanne) 2:80Google Scholar
  3. 3.
    Chen GH, Xu J, Yang YJ (2017) Exosomes: promising sacks for treating ischemic heart disease? Am J Physiol Heart Circ Physiol 313:H508–H523CrossRefGoogle Scholar
  4. 4.
    Chen J, Normand SL, Wang Y, Krumholz HM (2011) National and regional trends in heart failure hospitalization and mortality rates for medicare beneficiaries, 1998–2008. JAMA 306:1669–1678CrossRefGoogle Scholar
  5. 5.
    Wallukat G, Muller J, Hetzer R (2002) Specific removal of beta1-adrenergic autoantibodies from patients with idiopathic dilated cardiomyopathy. N Engl J Med 347:1806CrossRefGoogle Scholar
  6. 6.
    Patel PA, Hernandez AF (2013) Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy. Eur J Heart Fail 15:724–729CrossRefGoogle Scholar
  7. 7.
    Wallukat G, Schimke I (2014) Agonistic autoantibodies directed against G-protein-coupled receptors and their relationship to cardiovascular diseases. Semin Immunopathol 36:351–363CrossRefGoogle Scholar
  8. 8.
    Zuo L, Bao H, Tian J, Wang X, Zhang S, He Z, Yan L, Zhao R, Ma XL, Liu H (2011) Long-term active immunization with a synthetic peptide corresponding to the second extracellular loop of β1-adrenoceptor induces both morphological and functional cardiomyopathic changes in rats. Int J Cardiol 149:89–94CrossRefGoogle Scholar
  9. 9.
    Wang L, Hao H, Wang J, Wang X, Zhang S, Du Y, Lv T, Zuo L, Li Y, Liu H (2015) Decreased autophagy: a major factor for cardiomyocyte death induced by β1-adrenoceptor autoantibodies. Cell Death Dis 6:e1862CrossRefGoogle Scholar
  10. 10.
    Matsui S, Fu ML, Katsuda S, Hayase M, Yamaguchi N, Teraoka K, Kurihara T, Takekoshi N, Murakami E, Hoebeke J, Hjalmarson A (1997) Peptides derived from cardiovascular G-protein-coupled receptors induce morphological cardiomyopathic changes in immunized rabbits. J Mol Cell Cardiol 29:641–655CrossRefGoogle Scholar
  11. 11.
    Iwata M, Yoshikawa T, Baba A, Anzai T, Nakamura I, Wainai Y, Takahashi T, Ogawa S (2001) Autoimmunity against the second extracellular loop of beta(1)-adrenergic receptors induces beta-adrenergic receptor desensitization and myocardial hypertrophy in vivo. Circ Res 88:578–586CrossRefGoogle Scholar
  12. 12.
    Jahns R, Boivin V, Lohse MJ (2006) Beta1-adrenergic receptor-directed autoimmunity as a cause of dilated cardiomyopathy in rats. Int J Cardiol 112:7–14CrossRefGoogle Scholar
  13. 13.
    Bornholz B, Roggenbuck D, Jahns R, Boege F (2014) Diagnostic and therapeutic aspects of beta1-adrenergic receptor autoantibodies in human heart disease. Autoimmun Rev 13:954–962CrossRefGoogle Scholar
  14. 14.
    Dandel M, Wallukat G, Englert A, Hetzer R (2013) Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension. Atheroscler Suppl 14:203–211CrossRefGoogle Scholar
  15. 15.
    Wallukat G, Reinke P, Dorffel WV, Luther HP, Bestvater K, Felix SB, Baumann G (1996) Removal of autoantibodies in dilated cardiomyopathy by immunoadsorption. Int J Cardiol 54:191–195CrossRefGoogle Scholar
  16. 16.
    Li Y, Lei Y, Wagner E, Xie C, Lu W, Zhu J, Shen J, Wang J, Liu M (2013) Potent retro-inverso d-peptide for simultaneous targeting of angiogenic blood vasculature and tumor cells. Bioconjug Chem 24:133–143CrossRefGoogle Scholar
  17. 17.
    Menegatti S, Hussain M, Naik AD, Carbonell RG, Rao BM (2013) mRNA display selection and solid-phase synthesis of Fc-binding cyclic peptide affinity ligands. Biotechnol Bioeng 110:857–870CrossRefGoogle Scholar
  18. 18.
    Jahns R, Schlipp A, Boivin V, Lohse MJ (2010) Targeting receptor antibodies in immune cardiomyopathy. Semin Thromb Hemost 36:212–218CrossRefGoogle Scholar
  19. 19.
    Boivin V, Beyersdorf N, Palm D, Nikolaev VO, Schlipp A, Müller J, Schmidt D, Kocoski V, Kerkau T, Hünig T, Ertl G, Lohse MJ, Jahns R (2015) Novel receptor-derived cyclopeptides to treat heart failure caused by anti-β1-adrenoceptor antibodies in a human-analogous rat model. PLoS One 10:e0117589CrossRefGoogle Scholar
  20. 20.
    Okitsu K, Iritakenishi T, Imada T, Iwasaki M, Shibata SC, Fujino Y (2017) A longer total duration of rapid ventricular pacing does not increase the risk of postprocedural myocardial injury in patients who undergo transcatheter aortic valve implantation. Heart Vessels 32:1117–1122CrossRefGoogle Scholar
  21. 21.
    Nuamnaichati N, Sato VH, Moongkarndi P, Parichatikanond W, Mangmool S (2018) Sustained β-AR stimulation induces synthesis and secretion of growth factors in cardiac myocytes that affect on cardiac fibroblast activation. Life Sci 193:257–269CrossRefGoogle Scholar
  22. 22.
    Freedman NJ, Lefkowitz RJ (2004) Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation. J Clin Investig 113:1379–1382CrossRefGoogle Scholar
  23. 23.
    Hebert TE (2007) Anti-beta1AR antibodies in dilated cardiomyopathy: are these a new class of receptor agonists? Cardiovasc Res 76:5–7CrossRefGoogle Scholar
  24. 24.
    Brooks WW, Conrad CH (2009) Isoproterenol-induced myocardial injury and diastolic dysfunction in mice: structural and functional correlates. Comp Med 59:339–343PubMedPubMedCentralGoogle Scholar
  25. 25.
    Krenek P, Kmecova J, Kucerova D, Bajuszova Z, Musil P, Gazova A, Ochodnicky P, Klimas J, Kyselovic J (2009) Isoproterenol-induced heart failure in the rat is associated with nitric oxide-dependent functional alterations of cardiac function. Eur J Heart Fail 11:140–146CrossRefGoogle Scholar
  26. 26.
    Kamal FA, Watanabe K, Ma M, Abe Y, Elbarbary R, Kodama M, Aizawa Y (2011) A novel phenylpyridazinone, T-3999, reduces the progression of autoimmune myocarditis to dilated cardiomyopathy. Heart Vessels 26:81–90CrossRefGoogle Scholar
  27. 27.
    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 Investig 113:1419–1429CrossRefGoogle Scholar
  28. 28.
    Munch G, Boivin-Jahns V, Holthoff HP, Adler K, Lappo M, Truöl S, Degen H, Steiger N, Lohse MJ, Jahns R, Ungerer M (2012) Administration of the cyclic peptide COR-1 in humans (phase I study): ex vivo measurements of anti-beta1-adrenergic receptor antibody neutralization and of immune parameters. Eur J Heart Fail 14:1230–1239CrossRefGoogle Scholar
  29. 29.
    Li H, Zhang L, Huang B, Veitla V, Scherlag BJ, Cunningham MW, Aston CE, Kem DC, Yu X (2015) A peptidomimetic inhibitor suppresses the inducibility of beta1-adrenergic autoantibody-mediated cardiac arrhythmias in the rabbit. J Interv Card Electrophysiol 44:205–212CrossRefGoogle Scholar
  30. 30.
    Du Y, Yan L, Wang J, Zhan W, Song K, Han X, Li X, Cao J, Liu H (2012) β1-Adrenoceptor autoantibodies from DCM patients enhance the proliferation of T lymphocytes through the beta1-AR/cAMP/PKA and p38 MAPK pathways. Plos One 7:e52911CrossRefGoogle Scholar
  31. 31.
    Mason JM (2010) Design and development of peptides and peptide mimetics as antagonists for therapeutic intervention. Future Med Chem 2:1813–1822CrossRefGoogle Scholar
  32. 32.
    Nnane IP, Plotnikov AH, Peters G, Johnson M, Kojak C, Vutikullird A, Ariyawansa J, De Vries R, Davies BE (2016) Pharmacokinetics and safety of single intravenous doses of JNJ-54452840, an anti-beta1-adrenergic receptor antibody cyclopeptide, in healthy male Japanese and caucasian participants. Clin Pharmacokinet 55:225–236CrossRefGoogle Scholar
  33. 33.
    Rothermel BA, Hill JA (2008) Autophagy in load-induced heart disease. Circ Res 103:1363–1369CrossRefGoogle Scholar
  34. 34.
    Wang ZV, Rothermel BA, Hill JA (2010) Autophagy in hypertensive heart disease. J Biol Chem 285:8509–8514CrossRefGoogle Scholar
  35. 35.
    Wang X, Cui T (2017) Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy. Am J Physiol Heart Circ Physiol 313:H304–H319CrossRefGoogle Scholar
  36. 36.
    Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and beclin 1 in mediating autophagy. Circ Res 100:914–922CrossRefGoogle Scholar
  37. 37.
    Lai L, Chen J, Wang N, Zhu G, Duan X, Ling F (2017) MiRNA-30e mediated cardioprotection of ACE2 in rats with doxorubicin-induced heart failure through inhibiting cardiomyocytes autophagy. Life Sci 169:69–75CrossRefGoogle Scholar
  38. 38.
    Zhong Y, Zhong P, He S, Zhang Y, Tang L, Ling Y, Fu S, Tang Y, Yang P, Luo T, Chen B, Chen A, Wang X (2017) Trimetazidine protects cardiomyocytes against hypoxia/reoxygenation injury by promoting AMP-activated protein kinase-dependent autophagic flux. J Cardiovasc Pharmacol 69:389–397CrossRefGoogle Scholar
  39. 39.
    Wang L, Li Y, Ning N, Wang J, Yan Z, Zhang S, Jiao X, Wang X, Liu H (2018) Decreased autophagy induced by β1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis. Cell Death Dis 9:406CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Yu Dong
    • 1
    • 2
  • Yan Bai
    • 1
    • 2
  • Shangyue Zhang
    • 1
    • 2
  • Wenli Xu
    • 1
    • 2
  • Jiahui Xu
    • 1
    • 2
  • Yi Zhou
    • 1
    • 2
  • Suli Zhang
    • 1
    • 2
  • Ye Wu
    • 2
  • Haicun Yu
    • 1
    • 2
  • Ning Cao
    • 1
    • 2
  • Huirong Liu
    • 1
    • 2
    Email author
  • Wen Wang
    • 1
    • 2
    Email author
  1. 1.Department of Physiology and Pathophysiology, School of Basic Medical SciencesCapital Medical UniversityBeijingChina
  2. 2.Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular DiseasesCapital Medical UniversityBeijingChina

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