Proliferation in cardiac fibroblasts induced by β(1)-adrenoceptor autoantibody and the underlying mechanisms

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 β(1)-adrenoceptor autoantibody (β(1)-AA) in the sera of patients with various types of cardiovascular diseases decreased cardiac function. In the current study, we demonstrated that β(1)-AA impaired the cardiac function evaluated by echocardiography and that β(1)-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 β(1)-AA immunized mice model during 16 weeks. Further, we showed that β(1)-AA activated β(1)-AR/cAMP/PKA pathway and promoted proliferation in primary cardiac fibroblasts through specific binding to β(1)-AR but not to β(2)-AR. Moreover, β(1)-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 β(1)-AA was associated with lacking agonist-induced desensitization phenomena. The conditioned medium from β(1)-AA-stimulated cardiac fibroblasts induced cardiomyocyte apoptosis, which indicated that β(1)-AA changed the secretion of cardiac fibroblasts contributing to cardiac injury. These findings will contribute to our understanding of the pathological mechanisms of β(1)-AA.