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

Tingting Lv,Ning Cao,Yulin Gong,Yunhui Du,Wen Wang,Yan Bai,Suli Zhang,Huirong Liu

doi:10.1038/srep32430

Tingting Lv, Ning Cao + Show 6 more

Open Access

https://doi.org/10.1038/srep32430

Copy DOI

Journal: Scientific Reports	Publication Date: Aug 31, 2016
Citations: 39	License type: CC BY 4.0

Affiliation: Capital Medical University

Abstract

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.

Highlights

Higher in models of heart failure established by abdominal aortic coarctation or doxorubicin injection when myocardial fibrosis simultaneously occurred[20]
The spontaneous beating frequency of primary cultured neonatal rat cardiomyocytes was remarkly increased by stimulation of β1-AR mAb, which was blocked by β1-AR blocker metoprolol and β1-AR ECII peptide (Fig. S1D)
In the present study we demonstrate that the presence of β1-AA directly trigger cardiac dysfunction and collagen deposition in a β1-AR monoclonal antibody-positive mouse model

Summary

Introduction

Higher in models of heart failure established by abdominal aortic coarctation or doxorubicin injection when myocardial fibrosis simultaneously occurred[20]. Previous evidence showed that p38MAPK23 and ERK1/224 were involved in proliferation of cardiac fibroblasts. Our previous work suggested that β1-AA enhanced proliferation and secretion of lymphocytes through activating β1-AR/cAMP/PKA and p38MAPK25. Others’ research reported that β1-AA activated ERK1/2 in cardiomyocytes[26]. These experimental results, taken together with the expression of β1-AR on the surface of cardiac fibroblasts[27], suggested that β1-AA may be responsible for cardiac fibroblasts proliferation. This study was designed to establish a passive β1-AA immunized mice model to investigate the effect of β1-AA on myocardial fibrosis in vivo and to determine the impact of β1-AA on the proliferation and the underlying mechanisms in cultured cardiac fibroblasts in vitro. Our data will provide new experimental evidence for pathological mechanisms of β1-AA

Methods

Results

Conclusion