Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic β-Adrenergic Stimulation

Engelhardt, Stefan; Hein, Lutz; Dyachenkow, Vitaly; Kranias, Evangelia G.; Isenberg, Gerrit; Lohse, Martin J.

doi:10.1161/01.cir.0000117254.68497.39

Cited by 97 publications

(66 citation statements)

References 37 publications

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“…This increase in intracellular Ca 2+ probably is caused by a direct coupling of the α subunit of the stimulatory heterotrimeric guanine nucleotide-binding G protein to the Ca 2+ channel (25). Cardiomyopathic changes in ß 1 -adrenoceptoroverexpressing transgenic animals also could be rescued by phospholamban ablation which normalizes diastolic calcium levels (26), confirming that increased intracellular Ca 2+ is critical for the detrimental effects of β 1 -adrenergic stimulation (27). Our present study showed that β 1 -EC II IgG increased CaMKII phosphorylation and myocyte apoptosis.…”

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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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: 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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“…In marked contrast to results obtained from β 2 -subtype that needs a high level of expression to develop of heart failure, mice overexpressing β 1 -subtype, as low as five fold the endogenous expression level, present progressive hypertrophy and ventricular dysfunction, which culminate with heart failure by the age of 35 weeks (Engelhardt et al 1999). The pathways mediating the cardiac deleterious effects of β 1 -subtype overexpression seems to involve an altered calcium handling (Engelhardt et al 2001(Engelhardt et al , 2004) and increased Na + -H + exchanger (Engelhardt et al 2002). In addition, overexpression of β 1 -subtype in mice leads to upregulation of pro-apoptotic proteins, such as Bax (Bisognano et al 2000), and chronic stimulation of β 1 -subtype has been shown to increase rate of apoptosis (Communal et al 1998, Xiao 2001, Zhu et al 2001.…”

Section: Adrenergic Receptorsmentioning

confidence: 92%

Neurohumoral activation in heart failure: the role of adrenergic receptors

Brum

Rolim

Bacurau

et al. 2006

An. Acad. Bras. Ciênc.

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Heart failure (HF) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.

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“…25 These properties of MCT-rats are consistent with past reports for the same experimental model 27,28 and for other animal models of ventricular hypertrophy. 29 Thus, we are convinced that MCT-rats can serve as a model of ventricular hypertrophy to examine the propagation features of Ca 2+ waves.…”

Section: Mct-induced Rv Hypertrophymentioning

confidence: 94%

Acceleration of Ca2+ Waves in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat

Miura

Hirose

Endoh

et al. 2011

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp rrhythmias are likely to occur in diseased hearts, 1-3 and delayed afterdepolarizations (DADs) play an important role 4 in their occurrence, associated with catecholamine excess, 5 heart failure, 6 and mutations of the ryanodine receptor or calsequestrin. 7 Such diseased hearts not only exhibit an increase in diastolic intracellular Ca 2+ ([Ca 2+ ]i), 8 which causes spontaneous Ca 2+ release from the sarcoplasmic reticulum (SR), 9,10 but also exhibit nonuniform muscle contraction, 11,12 which causes Ca 2+ dissociation from the myofilaments within the border zone between contracting and stretched regions during the relaxation phase. 10,13,14 Both the Ca 2+ released from the SR and that dissociated from the myofilaments can induce Ca 2+ waves, which propagate along the myocardium by the mechanism of Ca 2+ -induced Ca 2+ release from the SR. 15 Since the velocity and amplitude of Ca 2+ waves determine the formation of DADs 16 (ie, arrhythmogenesis principally through the activation of the Na + -Ca 2+ exchange (NCX) current 16,17 ), it is still important to investigate the propagation features of the Ca 2+ waves.It has been reported that in ventricular hypertrophy, 6 clear changes occur with maladaptive remodeling of the myocardium: (1)

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Altered Calcium Handling Is Critically Involved in the Cardiotoxic Effects of Chronic β-Adrenergic Stimulation

Cited by 97 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

Neurohumoral activation in heart failure: the role of adrenergic receptors

Acceleration of Ca2+ Waves in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat

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