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Activin receptor-like kinase 4 (ALK4), a downstream receptor of transforming growth factor-β superfamily, is highly expressed in the mammal heart. We recently reported that ALK4 is upregulated in pressure-overloaded heart and ALK4 haplodeficiency attenuated the pressure overload-induced cardiac fibrosis. As we know, atrial fibrillation (AF) is often preceded by underlying cardiac disease causing ventricular pressure overload. Ventricular pressure overload increases atrial pressure and leads to atrial remodeling accompanied by AF inducibility. Therefore, it is very interesting to know whether ALK4 exert effects on the progression of atrial remodeling in the model of ventricular pressure overload and its association with vulnerability to AF.
Wild type (WT) littermates and ALK4+/- mice were subjected to abdominal aortic constriction (AAC) or sham operation. After four or eight weeks, echocardiographic measurements and hemodynamic measurements were made and inducibility of AF was tested. The hearts were either fixed in formalin for histological staining, or ventricles and atria were separated, weighted and snap-frozen for quantitative real-time PCR analysis.
ALK4 expression was gradually upregulated in both ventricle and atrium in AAC-induced cardiac hypertrophy and fibrosis in WT littermates over two-eight weeks post AAC, and reached summit at eight weeks post AAC. Compared with WT littermates, ALK4+/- mice demonstrated a similar extent of AAC-induced ventricular or atrial hypertrophy, but a significant suppression of ventricular fibrosis, and a subsequent amelioration in the cardiac dysfunction at both four and eight weeks post AAC. However, merely at eight weeks post AAC, changes in atrial remodeling in both WT littermates and ALK4+/- mice make a big difference. At eight weeks, compared to WT littermates, ALK4 haplodeficiency showed less extent of AAC-induced atrial fibrosis, less extent of reductions of Cx40 protein level and Cx40/Cx43 ratio as well as increase of Cx43 protein level in the atrial samples. Meanwhile, ALK4 haplodeficiency preserved AAC-induced decreased expressions of LTCC, KCND2, and KCNJ2 in atrium. Overall, programmed atrial stimulation showed ALK4 haplodeficiency had a significant protective effect against induction of AF in hypertrophied hearts. Mechanistically, ALK4 haploinsufficiency resulted in the suppression of Smad2/3 activity.
Our results demonstrate that ALK4 haploinsufficiency ameliorates atrial remodeling and vulnerability to AF in a mouse pressure-overload model associated with the suppression of Smad2/3 activity, and suggest that ALK4 is a novel therapeutic target in treating pressure overload-induced atrial remodeling and vulnerability to AF.