Proliferation in cardiac fibroblasts induced by ?1-adrenoceptor autoantibody and the underlying mechanisms.

ABSTRACT: Chronic sustained stimulation of ?-adrenoceptor is closely related to cardiac fibrosis which is bad for cardiac function. Growing evidence showed that the high prevalence of ?1-adrenoceptor autoantibody (?1-AA) in the sera of patients with various types of cardiovascular diseases decreased cardiac function. In the current study, we demonstrated that ?1-AA impaired the cardiac function evaluated by echocardiography and that ?1-AA triggered cardiac fibrosis in terms of increased expression of ?-smooth muscle actin as the marker of myofibroblast and collagen deposition in a passive ?1-AA immunized mice model during 16 weeks. Further, we showed that ?1-AA activated ?1-AR/cAMP/PKA pathway and promoted proliferation in primary cardiac fibroblasts through specific binding to ?1-AR but not to ?2-AR. Moreover, ?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 ?1-AA was associated with lacking agonist-induced desensitization phenomena. The conditioned medium from ?1-AA-stimulated cardiac fibroblasts induced cardiomyocyte apoptosis, which indicated that ?1-AA changed the secretion of cardiac fibroblasts contributing to cardiac injury. These findings will contribute to our understanding of the pathological mechanisms of ?1-AA.

SUBMITTER: Lv T 

PROVIDER: S-EPMC5006240 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature