β1-Adrenoceptor Autoantibodies from DCM Patients Enhance the Proliferation of T Lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK Pathways

Du, Yunhui; Li, Yan; Wang, Jin; Zhan, Wenzhang; Song, Kai; Han, Xue; Xiao, Li; Cao, Ji-Min; Liu, Huirong

doi:10.1371/journal.pone.0052911

Cited by 51 publications

(44 citation statements)

References 38 publications

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“…We previously demonstrated that β 1 -AA was likely to promote proliferation in T lymphocytes through p38MAPK25. Here we found that β 1 -AA increased the level of phosphorylated p38MAPK and ERK1/2 in cardiac fibroblast, which is similar to previous study.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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

Cao

et al. 2016

Sci Rep

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“…Further studies indicated that β 1 -AAbs displayed an analogous agonist effect mediated by β 1 -AR [4]. This process appears to contribute to heart failure and dilated cardiomyopathy [5,6]. We have shown that β 1 -AAbs are involved in ventricular arrhythmia formation in guinea pigs through activation of β 1 -AR.…”

Section: Introductionmentioning

confidence: 73%

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

Zuo

et al. 2015

International Journal of Cardiology

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“…A previous report demonstrated that β 1 AR-AAbs enhanced proliferation of rat CD3+ T lymphocytes in vitro, which was blocked by the selective β1AR antagonist metoprolol (42). β 1 AR-AAbs also inhibited the secretion of interferon-γ while promoting an increase in interleukin-4 levels.…”

Section: Discussionmentioning

confidence: 98%

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β 1 -Adrenergic Receptors

Nagatomo

McNamara

Alexis

et al. 2017

Journal of the American College of Cardiology

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BACKGROUND Among various cardiac autoantibodies (AAb), those recognizing the β1 adrenergic receptor (β1AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption. OBJECTIVES We investigated the role of β1AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy. METHODS Peripheral blood was drawn at enrollment in subjects with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; <6 months). Presence of IgG and IgG3-β1AR-AAb was determined and echocardiograms assessed at baseline and 6 months. Subjects were followed for up to 4 years. RESULTS Among the 353 enrolled subjects, 62 (18%) were positive for IgG3-β1AR-AAb (IgG3), 58 (16%) were positive for IgG but not IgG3 (non-IgG3), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. LV end-diastolic and end-systolic (LVEDD and LVESD, respectively) diameters were significantly larger in the non-IgG3 group compared to the other groups (LVEDD: p < 0.01; LVESD: p = 0.03). At 6 months, LVEF was significantly higher in the IgG3 group (p = 0.007). Multiple regression analysis demonstrated IgG3-β1AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, β = 0.20, p = 0.01; change in LVEF, β = 0.20, p = 0.008). In the subjects with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint. CONCLUSIONS IgG3-β1AR-AAb was associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy.

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β1-Adrenoceptor Autoantibodies from DCM Patients Enhance the Proliferation of T Lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK Pathways

Cited by 51 publications

References 38 publications

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

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

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

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β 1 -Adrenergic Receptors

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