Specific removal of β1-adrenoceptor autoantibodies by immunoabsorption in rabbits with autoimmune cardiomyopathy improved cardiac structure and function

Matsui, Shinobu; Larsson, Lisa; Hayase, Mituru; Katsuda, Shogo; Teraoka, Kohei; Kurihara, Takayuki; Murano, Hidekazu; Nishikawa, Katsuzou; Fu, Michael

doi:10.1016/j.yjmcc.2006.04.016

Cited by 18 publications

(8 citation statements)

References 34 publications

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“…This hypothesis is further supported by 3 major findings: 1) the antoantibodies exert agonistic and apoptotic effects in cultured cardiomyocytes (1,(4)(5)(6), 2) immunization with a synthetic peptide corresponding to a sequence in the second extracellular loop of the human adrenergic receptor (β 1 -EC II ) produces cardiomyopathy in a number of experimental animals (7)(8)(9)(10), and 3) removal of anti-β 1 -EC II antibodies improves cardiac function in the rabbit β 1 -EC II cardiomyopathy (11), and human dilated cardiomyopathy (12). Furthermore, isogenic transfer of sera from rats immunized with the β 1 -EC II peptide to healthy littermates produces cardiac morphology similar to the cardiomyopathic changes in the donor rats (9).…”

Section: Introductionmentioning

confidence: 77%

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Mao

Iwai

Fukuoka

et al. 2008

Journal of Molecular and Cellular Cardiology

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Auto-antibodies against the β 1 -adrenoceptors are present in 30−40% of patients with dilated cardiomyopathy. Recently, a synthetic peptide corresponding to a sequence of the second extracellular loop of the human β 1 -adrenoceptor (β 1 -EC II ) has been shown to produce endoplasmic reticulum (ER) stress, myocyte apoptosis and cardiomyopathy in immunized rabbits. To study the direct cardiac effects of anti-β 1 -EC II antibody in intact animals and if they are mediated via β 1 -adrenoceptor stimulation, we administered IgG purified from β 1 -EC II -immunized rabbits to recombination activating gene 2 knock-out (Rag2 −/− ) mice every two weeks with and without metoprolol treatment. Serial echocardiography and cardiac catheterization showed that β 1 -EC II IgG reduced cardiac systolic function after 3 months. This was associated with increase in heart weight, myocyte apoptosis, activation of caspase-3, -9 and -12, and increased ER stress as evidenced by upregulation of GRP78 and CHOP and cleavage of ATF6. The Rag2 −/− mice also exhibited increased phosphorylation of CaMKII and p38 MAPK. Metoprolol administration, which attenuated the phosphorylation of CaMKII and p38 MAPK, reduced the ER stress, caspase activation and cell death. Finally, we employed the small-interfering RNA technology to reduce caspase-12 in cultured rat cardiomyocytes. This reduced not only the increase of cleaved caspase-12 but also of the number of myocyte apoptosis produced by β 1 -EC II IgG. Thus, we conclude that ER stress plays an important role in cell death and cardiac dysfunction in β 1 -EC II IgG cardiomyopathy, and the effects of β 1 -EC II IgG are mediated via the β 1 -adrenergic receptor.

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Section: Introductionmentioning

confidence: 77%

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Mao

Iwai

Fukuoka

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…Animal models have played an important role in our understanding of the impact of these autoantibodies on human disease (3,9,11,12,17). These studies have primarily focused on their cardiomyopathic effects, whereas study of their impact on cardiac arrhythmias has been more complicated owing to the small heart size of smaller rodents and their difficulty in sustaining complex tachyarrhythmias compared with that observed in larger hearts in animals such as the dog or pig.…”

Section: Discussionmentioning

confidence: 99%

Inducible cardiac arrhythmias caused by enhanced β₁-adrenergic autoantibody expression in the rabbit

Scherlag

Kem

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Previous studies demonstrated burst pacing and intravenous infusion of ACh induced sustained atrial tachycardia when rabbits were immunized to produce ␤2-adrenergic receptor (␤2AR)-activating autoantibodies. The objective of this study was to examine the arrhythmogenic effect of ␤1-adrenergic receptor (␤1AR)-activating autoantibodies in the rabbit. Eight New Zealand white rabbits were immunized with a ␤1AR second extracellular loop peptide to raise ␤1AR antibody titers. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization. Arrhythmia occurrence was determined in response to burst pacing before and after ACh infusion in incremental concentrations of 10 M, 100 M, and 1 mM. The baseline sinus heart rate before and after immunization averaged 149 Ϯ 17 per min and 169 Ϯ 16 per min, respectively (P Ͻ 0.05). In the preimmune studies, there were five sustained (Ն10 s) arrhythmias in 32 induction attempts, which occurred in only four of eight rabbits. In the postimmune studies, there were 22 sustained arrhythmias in 32 induction attempts, which occurred in all eight rabbits (P Ͻ 0.0001 for the independent effect of immunization). Of the 22 sustained arrhythmias postimmunization, 15 were sinus tachycardia compared with only two before immunization (P Ͻ 0.01 for the independent effect of immunization). Postimmune (but not preimmune) rabbit sera demonstrated specific binding to ␤1AR and induced significant ␤1AR activation in transfected cells in vitro. No cross-reactivity with ␤2AR was observed. In conclusion, in contrast with rabbits with ␤2AR-activating autoantibodies that demonstrate predominantly atrial tachycardias, enhanced autoantibody activation of ␤1AR in the rabbit leads to tachyarrhythmias mainly in the form of sustained sinus tachycardia.

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“…4,10 Immunization of rodents against the second extracellular β 1 AR loop induce left ventricular dilation and dysfunction 11–13 among other effects compatible with chronic cardiac dysfunction. 14–16 Such effects are reversible upon removal of the antibodies, 17 transferable via serum transfusions, 12,16,18,19 and partially abrogated by β 1 AR antagonists 20 or synthetic mimics of the receptor epitope. 21–23 In DCM patients, the prevalence 3 and cAMP-stimulatory efficacy 24 of β 1 AR autoantibodies are correlated to more reduced cardiac function, 3 increased mortality, 25 more severe ventricular arrhythmia, 26 and sudden cardiac death.…”

Section: Introductionmentioning

confidence: 99%

“…27,28 Therefore, autoimmunity against the second extracellular loop of the β 1 AR is considered a cause or cofactor of chronic left ventricular dysfunction and a potential therapy target. 17,21–23,29–31 Interleucin 6 is suspected to play a key role in β 1 AR-induced autoimmune cardiomyopathy through enhancing antibody production. 32 Mechanisms, however, by which the antibodies modulate receptor function are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Impact of human autoantibodies on β1-adrenergic receptor conformation, activity, and internalization

Bornholz

Weidtkamp‐Peters

Schmitmeier

et al. 2012

Cardiovascular Research

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AimsAutoantibodies against second extracellular loops of β1-adrenergic receptors frequent in dilated cardiomyopathy confer myocardial dysfunction presumably via cAMP stimulation. Here, we investigate the autoantibody impact on receptor conformation and function.Methods and resultsIgG was prepared from patients with dilated cardiomyopathy, matched healthy donors (10 each) or commercial IgG preparations (2). IgG binding to β1-adrenergic receptor peptides was detected in 5 of 10 patients and 2 of 10 controls. IgG colocalization with the native receptor was detected in 8 of 10 patients and 1 of 10 controls (10 of 10 patients and 7 of 10 controls at >30 mg IgG/L). All IgGs exhibiting receptor colocalization triggered changes in receptor conformation (determined with fluorescent sensors) not stringently correlated to cAMP stimulation, suggesting the induction of more or less active receptor conformations. Receptor-activating IgG was detected in 8 of 10 patients but only 1 of 10 controls. In addition, IgG from 8 of 10 patients and 3 of 10 controls attenuated receptor internalization (measured by total internal reflection fluorescence microscopy). IgG-inducing inactive receptor conformations had no effect on subsequent cAMP stimulation by isoproterenol. IgG-inducing active receptor conformations dampened or augmented subsequent cAMP stimulation by isoproterenol, depending on whether receptor internalization was attenuated or not. Corresponding IgG effects on the basal beating rate and chronotropic isoproterenol response of embryonic human cardiomyocytes were observed.Conclusions(i) Autoantibodies trigger conformation changes in the β1-adrenergic receptor molecule. (ii) Some also attenuate receptor internalization. (iii) Combinations thereof increase the basal beating rate of cardiomyocytes and optionally entail dampening of their chronotropic catecholamine responses. (iv) The latter effects seem specific for patient autoantibodies, which also have higher levels.

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Specific removal of β1-adrenoceptor autoantibodies by immunoabsorption in rabbits with autoimmune cardiomyopathy improved cardiac structure and function

Cited by 18 publications

References 34 publications

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Inducible cardiac arrhythmias caused by enhanced β₁-adrenergic autoantibody expression in the rabbit

Impact of human autoantibodies on β1-adrenergic receptor conformation, activity, and internalization

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Specific removal of β1-adrenoceptor autoantibodies by immunoabsorption in rabbits with autoimmune cardiomyopathy improved cardiac structure and function

Cited by 18 publications

References 34 publications

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Inducible cardiac arrhythmias caused by enhanced β1-adrenergic autoantibody expression in the rabbit

Impact of human autoantibodies on β1-adrenergic receptor conformation, activity, and internalization

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Inducible cardiac arrhythmias caused by enhanced β₁-adrenergic autoantibody expression in the rabbit