Pro-arrhythmic action of autoantibodies against the second extracellular loop of β1-adrenoceptor and its underlying molecular mechanisms

Zuo, Li; Du, Yunhui; Ma, Jing; Wang, Ke; Zhao, Yuhui; Bai, Feng; Wu, Bo-Wei; Ma, Xin‐Liang; Liu, Huirong

doi:10.1016/j.ijcard.2015.06.144

Cited by 12 publications

(12 citation statements)

References 27 publications

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“…It was reported that the QT interval was prolonged in rats after long‐term active and passive immunization by β 1 ‐AAs (Zuo et al . ). This is different from the shortened QT c induced by β 1 ‐AR mAbs in isolated guinea‐pig hearts in this study.…”

Section: Discussionmentioning

confidence: 97%

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β₁‐Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea‐pigs

Zhao

Huang

Liu

et al. 2016

Experimental Physiology

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Section: Discussionmentioning

confidence: 97%

“…The main currents involved in the plateau and third phasese of the cardiac repolarization are I CaL and I K (Messineo, 1989). The β 1 -AAs increase I CaL (Fukuda et al 2004;Medei et al 2008;Zhao et al 2015;Zuo et al 2015) and I Kr (Zhaoet al 2015), but decrease I Ks by binding with β 1 -AR (Medei…”

Section: Discussionmentioning

confidence: 99%

β₁‐Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea‐pigs

Zhao

Huang

Liu

et al. 2016

Experimental Physiology

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“…More interestingly, β 1 -AA-induced increase in beating frequency of neonatal cardiomyocytes remained unchanged for more than 6 h lack of desensitization while ISO underwent desensitization within 60 minutes13. Badly, long term stimulation with β 1 -AA led to cardiac dysfunction1415, and even increased the susceptibility to arrhythmia1617 as well as sudden cardiac death1819. In particular, our previous data showed that the positive rate and titer of β 1 -AA were significantly higher in models of heart failure established by abdominal aortic coarctation or doxorubicin injection when myocardial fibrosis simultaneously occurred20.…”

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confidence: 98%

Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms

Cao

et al. 2016

Sci Rep

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Chronic sustained stimulation of β-adrenoceptor is closely related to cardiac fibrosis which is bad for cardiac function. Growing evidence showed that the high prevalence of β1-adrenoceptor autoantibody (β1-AA) in the sera of patients with various types of cardiovascular diseases decreased cardiac function. In the current study, we demonstrated that β1-AA impaired the cardiac function evaluated by echocardiography and that β1-AA triggered cardiac fibrosis in terms of increased expression of α-smooth muscle actin as the marker of myofibroblast and collagen deposition in a passive β1-AA immunized mice model during 16 weeks. Further, we showed that β1-AA activated β1-AR/cAMP/PKA pathway and promoted proliferation in primary cardiac fibroblasts through specific binding to β1-AR but not to β2-AR. Moreover, β1-AA was also likely to promote proliferation in cardiac fibroblasts through activating p38MAPK and ERK1/2 as p38MAPK inhibitor SB203580 and ERK1/2 inhibitor PD98059 partially reversed the proliferative effect. The persistent activating signalling of PKA and P38MAPK in 1 h induced by β1-AA was associated with lacking agonist-induced desensitization phenomena. The conditioned medium from β1-AA-stimulated cardiac fibroblasts induced cardiomyocyte apoptosis, which indicated that β1-AA changed the secretion of cardiac fibroblasts contributing to cardiac injury. These findings will contribute to our understanding of the pathological mechanisms of β1-AA.

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“…3 mice died in the immunized group within the first 12 weeks of protocol. Deaths occurred in animals presenting the most rapid increase in antibody titers, suggesting the occurrence of aabs-induced lethal arrhythmias3940. No alterations in body weight, food intake and behavior were observed in surviving mice.…”

Section: Resultsmentioning

confidence: 97%

MRI Assessment of Cardiomyopathy Induced by β1-Adrenoreceptor Autoantibodies and Protection Through β3-Adrenoreceptor Overexpression

Vanhoutte

Guilbaud

Martherus

et al. 2017

Sci Rep

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The cardiopathogenic role of autoantibodies (aabs) directed against β1-adrenoreceptors (β1-AR) is well established. In mouse models, they cause progressive dilated cardiomyopathy (DCM) whose characterization with echocardiography requires prolonged protocols with numerous animals, complicating the evaluation of new treatments. Here, we report on the characterization of β1-aabs-induced DCM in mice using 11.7T MRI. C57BL/6J mice (n = 10 per group) were immunized against the β1-AR and left ventricular (LV) systolic function was assessed at 10, 18 and 27 weeks. Increase in LV mass/tibial length ratio was detected as the first modification at 10 weeks together with dilation of cavities, thereby outperforming echocardiography. Significant impairment in diastolic index was also observed in immunized animals before the onset of systolic dysfunction. Morphometric and histological measurements confirmed these observations. The same protocol performed on β3-AR-overexpressing mice and wild-type littermates (n = 8–12 per group) showed that transgenic animals were protected with reduced LV/TL ratio compared to wild-type animals and maintenance of the diastolic index. This study demonstrates that MRI allows a precocious detection of the subtle myocardial dysfunction induced by β1-aabs and that β3-AR stimulation blunts the development of β1-aabs-induced DCM, thereby paving the way for the use of β3AR-stimulating drugs to treat this autoimmune cardiomyopathy.

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Pro-arrhythmic action of autoantibodies against the second extracellular loop of β1-adrenoceptor and its underlying molecular mechanisms

Cited by 12 publications

References 27 publications

β₁‐Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea‐pigs

β₁‐Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea‐pigs

Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms

MRI Assessment of Cardiomyopathy Induced by β1-Adrenoreceptor Autoantibodies and Protection Through β3-Adrenoreceptor Overexpression

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Pro-arrhythmic action of autoantibodies against the second extracellular loop of β1-adrenoceptor and its underlying molecular mechanisms

Cited by 12 publications

References 27 publications

β1‐Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea‐pigs

β1‐Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea‐pigs

Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms

MRI Assessment of Cardiomyopathy Induced by β1-Adrenoreceptor Autoantibodies and Protection Through β3-Adrenoreceptor Overexpression

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Product

Resources

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β₁‐Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea‐pigs

β₁‐Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea‐pigs