title: Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms.
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.
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Tingting
authors: T
authors: Lv
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.|Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing 100069, PR China.
authors: Yunhui
authors: Y
authors: Du
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Ning
authors: N
authors: Cao
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.|Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing 100069, PR China.
authors: Suli
authors: S
authors: Zhang
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Yulin
authors: Y
authors: Gong
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors: Yan
authors: Y
authors: Bai
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.|Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing 100069, PR China.
authors: Wen
authors: W
authors: Wang
authors: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.|Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing 100069, PR China.
authors: Huirong
authors: H
authors: Liu
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001323:Autoantibodies / Q000008:administration & dosage / Q000096:biosynthesis; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004452:Echocardiography; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D007116:Immunization, Passive; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D061251:Primary Cell Culture; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D000199:Actins; D001323:Autoantibodies; D005419:Flavonoids; D007093:Imidazoles; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011725:Pyridines; D018342:Receptors, Adrenergic, beta-1; D048051:p38 Mitogen-Activated Protein Kinases; C498862:Acta2 protein, rat; C535148:Mapk1 protein, mouse; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one