Agonistic Anti-β
            <sub>1</sub>
            -Adrenergic Receptor Autoantibodies From Cardiomyopathy Patients Reduce the β
            <sub>1</sub>
            -Adrenergic Receptor Expression in Neonatal Rat Cardiomyocytes

Podlowski, Svenia; Luther, Hans Peter; Morwinski, Rosemarie; Müller, Johannes; Wallukat, Gerd

doi:10.1161/01.cir.98.22.2470

Cited by 49 publications

(27 citation statements)

References 30 publications

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“…Radioligand binding assay of receptor density in crude membrane fraction revealed a trend of decrease (though statistically insignificant) in ␤ 1 AR density after 24-hour norepinephrine stimulation (Table 2), consistent with previous in vitro reports. 26 When compared with the response to short-term ␤ 1 AR stimulation (10 minutes), we found that sustained ␤ 1 AR stimulation was equally efficacious in mediating the positive inotropic and relaxant effects ( Figure 1). This observation is somewhat unexpected because it has been well established that cAMP/PKA signaling desensitizes within hours during prolonged ␤ 1 AR stimulation.…”

Section: Sustained ␤ 1 Ar Stimulation Induced Positive Inotropic and mentioning

confidence: 91%

Sustained β ₁ -Adrenergic Stimulation Modulates Cardiac Contractility by Ca ²⁺ /Calmodulin Kinase Signaling Pathway

Wang

Zhu

Wang

et al. 2004

Circulation Research

179

139

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A tenet of beta1-adrenergic receptor (beta1AR) signaling is that stimulation of the receptor activates the adenylate cyclase-cAMP-protein kinase A (PKA) pathway, resulting in positive inotropic and relaxant effects in the heart. However, recent studies have suggested the involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in beta1AR-stimulated cardiac apoptosis. In this study, we determined roles of CaMKII and PKA in sustained versus short-term beta1AR modulation of excitation-contraction (E-C) coupling in cardiac myocytes. Short-term (10-minute) and sustained (24-hour) beta1AR stimulation with norepinephrine similarly enhanced cell contraction and Ca2+ transients, in contrast to anticipated receptor desensitization. More importantly, the sustained responses were largely PKA-independent, and were sensitive to specific CaMKII inhibitors or adenoviral expression of a dominant-negative CaMKII mutant. Biochemical assays revealed that a progressive and persistent CaMKII activation was associated with a rapid desensitization of the cAMP/PKA signaling. Concomitantly, phosphorylation of phospholamban, an SR Ca2+ cycling regulatory protein, was shifted from its PKA site (16Ser) to CaMKII site (17Thr). Thus, beta1AR stimulation activates dual signaling pathways mediated by cAMP/PKA and CaMKII, the former undergoing desensitization and the latter exhibiting sensitization. This finding may bear important etiological and therapeutical ramifications in understanding beta1AR signaling in chronic heart failure.

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Section: Sustained ␤ 1 Ar Stimulation Induced Positive Inotropic and mentioning

confidence: 91%

Sustained β ₁ -Adrenergic Stimulation Modulates Cardiac Contractility by Ca ²⁺ /Calmodulin Kinase Signaling Pathway

Wang

Zhu

Wang

et al. 2004

Circulation Research

179

139

View full text Add to dashboard Cite

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“…14 However, prolonged exposure to this autoantibody for 72 h was able to decrease the β1-adrenergic receptor protein and mRNA content. 15 Cardiac dysfunction mimicking cardiomyopathy can be recapitulated by repeated immunization with peptides corresponding to the second extracellular loop of this receptor. After 6 months of immunization, we observed concentric hypertrophy accompanied by diastolic dysfunction and uncoupling of the β-adrenergic receptor.…”

Section: Adrenergic Receptormentioning

confidence: 99%

Autoimmune Mechanisms Underlying Dilated Cardiomyopathy

Yoshikawa

Baba

Nagatomo

2009

Circ J

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“…These cells can establish a spontaneous beating rhythm in culture and provide a model for cardiac function in humans (21)(22)(23)(24)(25). Celecoxib reduced the rate of beating in cardiomyocytes with significant effect occurring at 3 M and with an EC 50 of 7.7 M (Fig.…”

Section: A) Although 1 M Celecoxib Did Not Affect Rhythm In All Casesmentioning

confidence: 99%

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

Frolov

Berim

Singh

2008

Journal of Biological Chemistry

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Selective inhibitors of cyclooxygenase-2 (COX-2), such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), have been developed for treating arthritis and other musculoskeletal complaints. Selective inhibition of COX-2 over COX-1 results in preferential decrease in prostacyclin production over thromboxane A2 production, thus leading to less gastric effects than those seen with nonselective COX inhibitors such as acetylsalicylic acid (aspirin). Here we show a novel effect of celecoxib via a mechanism that is independent of COX-2 inhibition. The drug inhibited the delayed rectifier (Kv2) potassium channels from Drosophila, rats, and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture. These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid, a potent inhibitor of both COX-1 and COX-2, to inhibit rat Kv2.1 channels. A genetically null mutant of Drosophila Shab (Kv2) channels reproduced the cardiac effect of celecoxib, and the drug was unable to further enhance the effect of the mutation. These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats, implicating the inhibition of Kv2 channels as the mechanism underlying this effect.Selective COX-2 2 inhibitors, or coxibs, were developed for use as nonsteroidal anti-inflammatory drugs without adverse gastric effects (1, 2). Gastric effects of nonselective cyclooxygenase inhibitors, such as acetylsalicylic acid (aspirin), arise in main part from inhibition of cyclooxygenase-1. A selective inhibition of COX-2 by coxibs helps avoid these effects (3, 4); however, adverse cardiovascular effects complicate the use of coxibs (5-7). These effects of coxibs have been attributed to a reduction in antithrombotic, COX-2-derived prostacyclin without a reduction in prothrombotic, COX-1-derived platelet thromboxane. This shifts the balance toward a prothrombotic state resulting in clot formation (7).The adverse effects of drugs like celecoxib arising from their selective inhibition of COX-2 is currently the topic of intense discussion (7,8). We now show that celecoxib can have additional, heretofore unanticipated effects on Drosophila hearts and rat heart cells via a pathway independent of cyclooxygenase inhibition. At low micromolar concentrations, celecoxib reduced heart rate and induced pronounced arrhythmia in Drosophila hearts. A similar effect was observed in rat cardiomyocytes in culture in which the drug reduced the beating rate in clusters of cells and made the beating arrhythmic. These effects were not mediated via cyclooxygenase inhibition but involved inhibition of the voltage-activated delayed rectifier K ϩ channels (Kv2) by the drug. These observations reveal a new molecular mechanism underlying the effects of celecoxib that may operate in addition to its prothrombotic influence. The data also raise the possibility of effects on other tissues that express Kv2 channels. EXPERIM...

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Agonistic Anti-β ₁ -Adrenergic Receptor Autoantibodies From Cardiomyopathy Patients Reduce the β ₁ -Adrenergic Receptor Expression in Neonatal Rat Cardiomyocytes

Abstract: We conclude that after longer-term treatment with the anti-beta1-adrenergic receptor autoantibodies, the rat cardiomyocytes showed a beta-adrenergic receptor expression similar to that observed in failing hearts from patients with dilated cardiomyopathy.

Cited by 49 publications

References 30 publications

Sustained β ₁ -Adrenergic Stimulation Modulates Cardiac Contractility by Ca ²⁺ /Calmodulin Kinase Signaling Pathway

Sustained β ₁ -Adrenergic Stimulation Modulates Cardiac Contractility by Ca ²⁺ /Calmodulin Kinase Signaling Pathway

Autoimmune Mechanisms Underlying Dilated Cardiomyopathy

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

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Agonistic Anti-β 1 -Adrenergic Receptor Autoantibodies From Cardiomyopathy Patients Reduce the β 1 -Adrenergic Receptor Expression in Neonatal Rat Cardiomyocytes

Abstract: We conclude that after longer-term treatment with the anti-beta1-adrenergic receptor autoantibodies, the rat cardiomyocytes showed a beta-adrenergic receptor expression similar to that observed in failing hearts from patients with dilated cardiomyopathy.

Cited by 49 publications

References 30 publications

Sustained β 1 -Adrenergic Stimulation Modulates Cardiac Contractility by Ca 2+ /Calmodulin Kinase Signaling Pathway

Sustained β 1 -Adrenergic Stimulation Modulates Cardiac Contractility by Ca 2+ /Calmodulin Kinase Signaling Pathway

Autoimmune Mechanisms Underlying Dilated Cardiomyopathy

Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

Contact Info

Product

Resources

About

Agonistic Anti-β ₁ -Adrenergic Receptor Autoantibodies From Cardiomyopathy Patients Reduce the β ₁ -Adrenergic Receptor Expression in Neonatal Rat Cardiomyocytes

Sustained β ₁ -Adrenergic Stimulation Modulates Cardiac Contractility by Ca ²⁺ /Calmodulin Kinase Signaling Pathway

Sustained β ₁ -Adrenergic Stimulation Modulates Cardiac Contractility by Ca ²⁺ /Calmodulin Kinase Signaling Pathway