β1-Adrenoceptor antibodies induce apoptosis in adult isolated cardiomyocytes

Staudt, Yvonne; Mobini, Reza; Fu, Michael; Felix, Stephan B.; Kühn, Jens Peter; Staudt, Alexander

doi:10.1016/s0014-2999(03)01431-6

Cited by 76 publications

(46 citation statements)

References 22 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: 58%

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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: 58%

“…The β 1 -EC II antibody has been shown to stimulate the β 1 -adrenoceptor and increase cAMP/ protein kinase A (PKA) acutely in cultured cardiomyocytes, and these effects are abolished by metoprolol (6). Previously, cAMP/PKA was thought to play a role in the β 1 -adrenergically induced myocyte apoptosis (22).…”

Section: Discussionmentioning

confidence: 99%

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 ␤ 1 -AR-mediated apoptotic effect of the ␤ 1 -EC II antibodies also has been shown directly in adult isolated cardiomyocytes, using metoprolol pretreatment (28). Studies are now in progress in our laboratory to show whether the protective effects of metoprolol on cardiac dysfunction and myocyte apoptosis in the autoimmune cardiomyopathy are associated functionally with attenuation of the CaMKII, p38 MAPK, and ER stress signals.…”

Section: Discussionmentioning

confidence: 91%

“…The importance of the ␤ 1 -AR antibody in heart failure has been established by direct demonstration of dilated cardiomyopathy in animals immunized with a peptide corresponding to the sequence of the second extracellular loop of the ␤ 1 -AR (␤ 1 -EC II ) (8, 21). In addition, the ␤ 1 -EC II antisera obtained from the experimental animals have been shown to be biologically active (28,29), with a proapoptotic action via activation of the ␤ 1 -AR on cultured cardiomyocytes (28). However, little is known about how the anti-␤ 1 -EC II antibody exerts its cardiodepressant effects distal to the ␤ 1 -AR site or whether the ␤ 1 -EC II -induced cardiomyopathy is affected by increased norepinephrine (NE).…”

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confidence: 99%

Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine

Mao

Fukuoka²,

Iwai³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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-s. Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine. Am J Physiol Heart Circ Physiol 293: H1636-H1645, 2007. First published June 1, 2007; doi:10.1152 doi:10. /ajpheart.01377.2006 suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the ␤ 1-adrenergic receptor (␤1-ECII) is mediated via a biologically active anti-␤ 1-ECII antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the ␤ 1-ECII autoantibody is a partial ␤1-agonist, we speculate that the cardiomyopathy is produced by the ␤ 1-receptormediated stimulation of the CaMKII-p38 MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive ␤ 1-ECII immunization, sham immunization, NE pellet, or ␤ 1-ECII immunization plus NE pellet for 6 mo. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by terminal deoxytransferasemediated dUTP nick-end labeling and caspase-3 activity, whereas CaMKII, MAPK family (JNK, p38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry, and kinase activity assay. ␤ 1-ECII immunization produced progressive LV dilation, systolic dysfunction, and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP and increased cleavage of caspase-12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB 203580 abolished the induction of ER stress and cell apoptosis produced by the ␤ 1-ECII antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by ␤ 1-ECII peptide, and this is enhanced by increased NE and caused by activation of the ␤ 1-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.cardiomyocytes; signal transduction EVIDENCE HAS ACCUMULATED indicating that autoimmunity plays an important role in viral myocarditis and dilated cardiomyopathy (18). Among the various known anti-heart autoantibodies, an antibody activating the human ␤ 1 -adrenergic receptor (␤ 1 -AR) has been best studied. The autoantibody is not only present in 30 -40% of patients with dilated cardiomyopathy (7,20) but also has been shown to predict increased mortality in the patients (30). The importance of the ␤ 1 -AR antibody in heart failure has been established by direct demonstration of dilated cardiomyopathy in animals immunized with a peptide corresponding to the sequence of the second extracellular loop of the ␤ 1 -AR (␤ 1 -EC II ) (8, 21). In addition, the ␤ 1 -EC II antisera obtained from the experimental animals have been shown to be biologically active (28,29), with a proapoptotic action via activation of the...

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“…20 Beta-1 adrenergic receptor autoantibodies can induce apoptosis in isolated myocytes and exert a similar effect in vivo, causing myocardial dysfunction. 24,25 Antibodies against the Na Antibodies against intracellular proteins form after injury has exposed the circulation to these proteins that typically would not be recognized by the immune system. 28 For example, antibodies against myosin and troponin I have been reported to be present in experimental models of autoimmune myocarditis, 29,30 in humans with dilated CMP, and in ischemic heart disease.…”

Section: Antibody Production and Heart Failurementioning

confidence: 99%