Activin Receptor-Like Kinase 4 Haplodeficiency Mitigates Arrhythmogenic Atrial Remodeling and Vulnerability to Atrial Fibrillation in Cardiac Pathological Hypertrophy

• Published in: Journal of the American Heart Association Vol. 7; no. 16; p. e008842
• Main Authors: Wang, Qian, Chen, Yihe, Zhang, Daoliang, Li, Changyi, Chen, Xiaoqing, Hou, Jianwen, Fei, Yudong, Wang, Yuepeng, Li, Yigang
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 21.08.2018; Wiley
• Subjects: Activin Receptors, Type I - genetics; Activin Receptors, Type I - metabolism; Aged; ALK4; Animals; Aorta, Abdominal - surgery; atrial fibrillation; Atrial Fibrillation - genetics; Atrial Remodeling - genetics; cardiac hypertrophy; Cardiomegaly; Chemokine CCL2 - metabolism; Chemotactic Factors - metabolism; Connexin 43 - metabolism; Connexins - metabolism; Female; Fibrosis; Gap Junction alpha-5 Protein; Genetic Predisposition to Disease; Haploinsufficiency; Heart Conduction System; Humans; Hypertension; Interleukin-6 - metabolism; Male; Mice; Middle Aged; Myocytes, Cardiac - metabolism; Original Research; Patch-Clamp Techniques; Smad2 Protein - metabolism; Smad2/3; Smad3 Protein - metabolism; structural and electrical remodeling; atrial fibrillation; ALK4; Smad2/3; cardiac hypertrophy; structural and electrical remodeling
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/jaha.118.008842

Background Activin receptor-like kinase 4 ( ALK 4) is highly expressed in mammal heart. Atrial fibrillation ( AF ) is closely related to ventricular pressure overload. Because pressure overload increases atrial pressure and leads to atrial remodeling, it would be informative to know whether ALK 4 exerts potential effects on atrial remodeling and AF vulnerability in a pressure-overload model. Methods and Results Wild-type littermates and ALK 4 mice were subjected to abdominal aortic constriction or a sham operation. After 4 or 8 weeks, echocardiographic and hemodynamic measurements were performed, and inducibility of AF was tested. The hearts were divided into atria and ventricles and then were fixed in formalin for staining, or they were weighted and snap-frozen for quantitative real-time polymerase chain reaction and Western blot analysis. Compared with wild-type littermates, ALK 4 mice demonstrated a similar extent of atrial hypertrophy but significantly suppressed atrial fibrosis at 8 weeks post-abdominal aortic constriction. ALK 4 haplodeficiency partially blocked abdominal aortic constriction-induced upregulation of monocyte chemotactic protein 1 and interleukin-6, and the increased chemotaxin of macrophages. ALK 4 haplodeficiency also blunted a reduction of connexin 40 and redistribution of connexin 43 from the intercalated disk to the lateral membranes, thereby improving localized conduction abnormalities. Meanwhile, ALK 4 haplodeficiency inhibited abdominal aortic constriction-induced decreased I , I and I densities as well as the accompanying action potential duration shortening. Mechanistically, ALK 4 haploinsufficiency resulted in the suppression of Smad2/3 activity in this model. Conclusions Our results demonstrate that ALK 4 haplodeficiency ameliorates atrial remodeling and vulnerability to AF in a pressure-overload model through inactivation of the Smad2/3 pathway, suggesting that ALK 4 might be a potential therapeutic target in combating pressure overload-induced AF .