Anti-β1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: Mapping of epitopes in the first and second extracellular loops

Wallukat, Gerd; Wollenberger, A; Morwinski, Rosemarie; Pitschner, Heinz-Friedrich

doi:10.1016/s0022-2828(08)80036-3

Cited by 181 publications

(141 citation statements)

References 37 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: 61%

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: 61%

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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“…The pathogenic properties of desmin-mutation were shown in a mouse model for desminopathy as well; transgenic mice with a 7-amino acid deletion (D7-des) exhibited structural defects of the myocardium that resembled human desminrelated cardiomyopathy with aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates that were desmin-positive [32]. Abnormalities of the humoral immune system are present in patients with DCM, and various antibodies have been identified in DCM [2][3][4][5][6][7]. Animal models further indicate that under certain pathological conditions, DCM can be triggered by autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

“…Disturbances in humoral immunity play an important role in cardiac dysfunction of DCM patients. A number of autoantibodies against cardiac cell proteins have been identified in DCM: e.g., antibodies against the cardiac beta-1 adrenergic receptor, contractile proteins, mitochondrial proteins and the muscarinic acetylcholine receptor-2 [2][3][4][5][6][7]. Experimental and clinical data indicate that cardiac antibodies play an active role in the pathogenesis of DCM and may contribute to cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

et al. 2007

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Cardiac autoantibodies play a pathogenic role in dilated cardiomyopathy (DCM). Removal of antibodies by immunoadsorption (IA) induces hemodynamic improvement in DCM patients. The present study investigated the effects of IA on myocardial gene expression of the intermediate cytoskeletal filament desmin, which is upregulated in heart failure. RNA was isolated from five explanted nonfailing hearts and five explanted failing hearts of DCM patients, and myocardial gene expression of desmin was estimated by real-time polymerase chain reaction (PCR). In a case-control study in six DCM patients (LVEF < 40%,

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“…Isolation, cultivation, and detection procedures have been described in detail previously. 13 The doseresponse relationship between activating IgG or angiotensin II concentration and the spontaneous beating rate is linear.…”

Section: Bioassays and Analysis Of Epitopesmentioning

confidence: 99%

Angiotensin II Type 1–Receptor Activating Antibodies in Renal-Allograft Rejection

Dragun

Müller

Bräsen³

et al. 2005

N Engl J Med

766

684

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Anti-β1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: Mapping of epitopes in the first and second extracellular loops

Cited by 181 publications

References 37 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

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

Angiotensin II Type 1–Receptor Activating Antibodies in Renal-Allograft Rejection

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