Expression And Effect Of TGF-β1/Smad/α-actinin-2/Kv1.5 Signaling Pathway In The Atrial Myocardium Of Patients With Atrial Fibrillation

Background and ObjectiveAtrial remodeling plays a critical role in the occurrence and development of atrial fibrillation(AF). Atrial remodeling consists of structural and electrical remodeling. TGF-β1/Smad pathway induced atrial fibrosis is associated with structural remodeling. Cytoskeleton might change in the process of atrial structural remodeling and α-actinin-2 is a critical component of cytoskeleton. The Kv1.5 channel belongs to the ultra-rapid delayed rectifier potassium current and is reportedly related to atrial electrical remodeling. However, the links between atrial structural remodeling and atrial electrical remodeling remain unclear. This study investigated the expression of TGF-β1/Smad/α-actinin-2/Kv1.5 signaling pathway in the atrial myocardium of patients with AF, and discuss the relationship between atrial structural remodeling and atrial electrical remodeling.MethodsForty-one right atrial specimens obtained from patients with rheumatic heart disease( RHD) requiring valve replacement surgery were divided into the chronic atrial fibrillation(RHD+cAF; n = 29) and sinus rhythm(RHD+sinus rhythm; n = 12) groups. Patients with congenital heart disease and sinus rhythm(CHD+sinus rhythm) who underwent heart surgery served as controls(n = 10). Echocardiography was used to measure cardiac cavity size and analyze cardiac function. Atrial fibrosis in the atrial specimens was examined by hematoxylin and eosin as well as Masson’s trichrome staining. Atrial ultrastructure was observed by Transmission electron microscopy(TEM).The mRNA and protein levels of TGF-β1, Smad2/p-Smad2, Smad7, Kv1.5, and α-actinin-2 were investigated using quantitative real-time PCR, immunohistochemistry, and western blotting.Results(1) The histology results revealed collagen fiber expression increased gradually, with reduced expression in the CHD+sinus rhythm group and increased expression in the RHD+sinus rhythm and RHD+cAF groups.(P < 0.05)(2) Neatly arranged myofibers and completed sarcomeres were visible on images of the control group. Vague and ruptured sarcomeres of varying lengths, and clustered mitochondria, were observed in the RHD+sinus rhythm and RHD+cAF group.(3) The mRNA and protein expression levels of TGF-β1, Smad2/p-Smad2, Smad7, Kv1.5, and α-actinin-2 in the RHD+cAF group were significantly higher than those in the RHD+sinus rhythm and CHD+sinus rhythm groups(P<0.05)(4) Correlation analysis showed that the expression of α-actinin-2 was correlated with the CVF,TGF-β1,Kv1.5 level, respectively.Conclusion(1) The TGF-β1/Smad/α-actinin-2/Kv1.5 signaling pathway participates in AF pathogenesis in patients with RHD.(2) TGF-β1/Smad, a vital signal involved in structural remodeling related to atrial fibrosis, may regulate Kv1.5 ion channel induced electrical remodeling via α-actinin-2.