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

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

doi:10.1038/srep32430

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

Sci Rep. 2016 Aug 31:6:32430. doi: 10.1038/srep32430.

Authors

Tingting Lv¹, Yunhui Du^{1

2}, Ning Cao¹, Suli Zhang^{1

2}, Yulin Gong¹, Yan Bai¹, Wen Wang^{1

2}, Huirong Liu^{1

2}

Affiliations

¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
² Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing 100069, PR China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / genetics
Actins / immunology
Amino Acid Sequence
Animals
Animals, Newborn
Autoantibodies / administration & dosage
Autoantibodies / biosynthesis
Cell Line
Cell Proliferation / drug effects
Echocardiography
Endomyocardial Fibrosis / etiology
Endomyocardial Fibrosis / genetics
Endomyocardial Fibrosis / immunology*
Endomyocardial Fibrosis / pathology
Fibroblasts / drug effects
Fibroblasts / immunology*
Fibroblasts / pathology
Flavonoids / pharmacology
Gene Expression Regulation
Imidazoles / pharmacology
Immunization, Passive
Mice
Mice, Inbred BALB C
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / immunology
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / immunology
Myocardium / immunology*
Myocardium / pathology
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / immunology*
Myocytes, Cardiac / pathology
Primary Cell Culture
Pyridines / pharmacology
Rats
Receptors, Adrenergic, beta-1 / genetics*
Receptors, Adrenergic, beta-1 / immunology
Signal Transduction
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / immunology

Substances

Actins
Autoantibodies
Flavonoids
Imidazoles
Pyridines
Receptors, Adrenergic, beta-1
smooth muscle actin, rat
Mapk1 protein, mouse
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
p38 Mitogen-Activated Protein Kinases
SB 203580
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one