Skip to main content
Top
Published in: Heart and Vessels 6/2019

01-06-2019 | Original Article

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

Authors: Yu Dong, Yan Bai, Shangyue Zhang, Wenli Xu, Jiahui Xu, Yi Zhou, Suli Zhang, Ye Wu, Haicun Yu, Ning Cao, Huirong Liu, Wen Wang

Published in: Heart and Vessels | Issue 6/2019

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
go back to reference 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 23:792–800CrossRefPubMed 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 23:792–800CrossRefPubMed
2.
go back to reference 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) 2:80 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) 2:80
3.
go back to reference Chen GH, Xu J, Yang YJ (2017) Exosomes: promising sacks for treating ischemic heart disease? Am J Physiol Heart Circ Physiol 313:H508–H523CrossRefPubMed Chen GH, Xu J, Yang YJ (2017) Exosomes: promising sacks for treating ischemic heart disease? Am J Physiol Heart Circ Physiol 313:H508–H523CrossRefPubMed
4.
go back to reference 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 306:1669–1678CrossRefPubMedPubMedCentral 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 306:1669–1678CrossRefPubMedPubMedCentral
5.
go back to reference Wallukat G, Muller J, Hetzer R (2002) Specific removal of beta1-adrenergic autoantibodies from patients with idiopathic dilated cardiomyopathy. N Engl J Med 347:1806CrossRefPubMed Wallukat G, Muller J, Hetzer R (2002) Specific removal of beta1-adrenergic autoantibodies from patients with idiopathic dilated cardiomyopathy. N Engl J Med 347:1806CrossRefPubMed
7.
go back to reference Wallukat G, Schimke I (2014) Agonistic autoantibodies directed against G-protein-coupled receptors and their relationship to cardiovascular diseases. Semin Immunopathol 36:351–363CrossRefPubMed Wallukat G, Schimke I (2014) Agonistic autoantibodies directed against G-protein-coupled receptors and their relationship to cardiovascular diseases. Semin Immunopathol 36:351–363CrossRefPubMed
8.
go back to reference 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 149:89–94CrossRefPubMed 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 149:89–94CrossRefPubMed
9.
go back to reference 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:e1862CrossRefPubMedPubMedCentral 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:e1862CrossRefPubMedPubMedCentral
10.
go back to reference 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 29:641–655CrossRefPubMed 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 29:641–655CrossRefPubMed
11.
go back to reference 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 88:578–586CrossRefPubMed 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 88:578–586CrossRefPubMed
12.
go back to reference Jahns R, Boivin V, Lohse MJ (2006) Beta1-adrenergic receptor-directed autoimmunity as a cause of dilated cardiomyopathy in rats. Int J Cardiol 112:7–14CrossRefPubMed Jahns R, Boivin V, Lohse MJ (2006) Beta1-adrenergic receptor-directed autoimmunity as a cause of dilated cardiomyopathy in rats. Int J Cardiol 112:7–14CrossRefPubMed
13.
go back to reference Bornholz B, Roggenbuck D, Jahns R, Boege F (2014) Diagnostic and therapeutic aspects of beta1-adrenergic receptor autoantibodies in human heart disease. Autoimmun Rev 13:954–962CrossRefPubMed Bornholz B, Roggenbuck D, Jahns R, Boege F (2014) Diagnostic and therapeutic aspects of beta1-adrenergic receptor autoantibodies in human heart disease. Autoimmun Rev 13:954–962CrossRefPubMed
14.
go back to reference Dandel M, Wallukat G, Englert A, Hetzer R (2013) Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension. Atheroscler Suppl 14:203–211CrossRefPubMed Dandel M, Wallukat G, Englert A, Hetzer R (2013) Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension. Atheroscler Suppl 14:203–211CrossRefPubMed
15.
go back to reference 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 54:191–195CrossRefPubMed 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 54:191–195CrossRefPubMed
16.
go back to reference 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 24:133–143CrossRefPubMed 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 24:133–143CrossRefPubMed
17.
go back to reference 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 110:857–870CrossRefPubMed 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 110:857–870CrossRefPubMed
18.
go back to reference Jahns R, Schlipp A, Boivin V, Lohse MJ (2010) Targeting receptor antibodies in immune cardiomyopathy. Semin Thromb Hemost 36:212–218CrossRefPubMed Jahns R, Schlipp A, Boivin V, Lohse MJ (2010) Targeting receptor antibodies in immune cardiomyopathy. Semin Thromb Hemost 36:212–218CrossRefPubMed
19.
go back to reference 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:e0117589CrossRefPubMedPubMedCentral 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:e0117589CrossRefPubMedPubMedCentral
20.
go back to reference 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 32:1117–1122CrossRefPubMed 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 32:1117–1122CrossRefPubMed
21.
go back to reference 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 193:257–269CrossRefPubMed 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 193:257–269CrossRefPubMed
22.
go back to reference Freedman NJ, Lefkowitz RJ (2004) Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation. J Clin Investig 113:1379–1382CrossRefPubMed Freedman NJ, Lefkowitz RJ (2004) Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation. J Clin Investig 113:1379–1382CrossRefPubMed
23.
go back to reference Hebert TE (2007) Anti-beta1AR antibodies in dilated cardiomyopathy: are these a new class of receptor agonists? Cardiovasc Res 76:5–7CrossRefPubMed Hebert TE (2007) Anti-beta1AR antibodies in dilated cardiomyopathy: are these a new class of receptor agonists? Cardiovasc Res 76:5–7CrossRefPubMed
24.
go back to reference Brooks WW, Conrad CH (2009) Isoproterenol-induced myocardial injury and diastolic dysfunction in mice: structural and functional correlates. Comp Med 59:339–343PubMedPubMedCentral Brooks WW, Conrad CH (2009) Isoproterenol-induced myocardial injury and diastolic dysfunction in mice: structural and functional correlates. Comp Med 59:339–343PubMedPubMedCentral
25.
go back to reference 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 11:140–146CrossRefPubMedPubMedCentral 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 11:140–146CrossRefPubMedPubMedCentral
26.
go back to reference 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 26:81–90CrossRefPubMed 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 26:81–90CrossRefPubMed
27.
go back to reference 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 113:1419–1429CrossRefPubMed 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 113:1419–1429CrossRefPubMed
28.
go back to reference 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 14:1230–1239CrossRefPubMed 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 14:1230–1239CrossRefPubMed
29.
go back to reference 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 44:205–212CrossRefPubMedPubMedCentral 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 44:205–212CrossRefPubMedPubMedCentral
30.
go back to reference 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:e52911CrossRefPubMedPubMedCentral 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:e52911CrossRefPubMedPubMedCentral
31.
go back to reference Mason JM (2010) Design and development of peptides and peptide mimetics as antagonists for therapeutic intervention. Future Med Chem 2:1813–1822CrossRefPubMed Mason JM (2010) Design and development of peptides and peptide mimetics as antagonists for therapeutic intervention. Future Med Chem 2:1813–1822CrossRefPubMed
32.
go back to reference 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 55:225–236CrossRefPubMed 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 55:225–236CrossRefPubMed
35.
36.
go back to reference 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 100:914–922CrossRef 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 100:914–922CrossRef
37.
go back to reference 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 169:69–75CrossRefPubMed 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 169:69–75CrossRefPubMed
38.
go back to reference 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 69:389–397CrossRefPubMed 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 69:389–397CrossRefPubMed
39.
go back to reference 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 9:406CrossRefPubMedPubMedCentral 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 9:406CrossRefPubMedPubMedCentral
Metadata
Title
Cyclic peptide RD808 reduces myocardial injury induced by β1-adrenoreceptor autoantibodies
Authors
Yu Dong
Yan Bai
Shangyue Zhang
Wenli Xu
Jiahui Xu
Yi Zhou
Suli Zhang
Ye Wu
Haicun Yu
Ning Cao
Huirong Liu
Wen Wang
Publication date
01-06-2019
Publisher
Springer Japan
Published in
Heart and Vessels / Issue 6/2019
Print ISSN: 0910-8327
Electronic ISSN: 1615-2573
DOI
https://doi.org/10.1007/s00380-018-1321-3

Other articles of this Issue 6/2019

Heart and Vessels 6/2019 Go to the issue