Rongjie Lin1, Shaohui Wu1, Dan Zhu2, Mu Qin3, Xu Liu4. 1. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. 2. Department of Cardiac Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. 3. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. Electronic address: qinmu-1001@live.cn. 4. Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. Electronic address: heartlx@sina.com.
Abstract
AIMS: Atrial fibrosis is a common feature of atrial fibrillation (AF). Recently, it is reported that osteopontin (OPN) can induce fibrosis in lungs, livers and kidneys. However, its role in atrial fibrosis remains unclear. Here, we sought to determine the involvement of OPN in atrial fibrosis and the underlying mechanisms during this pathological remodeling process. MATERIALS AND METHODS: Protein expressions were determined by enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining and immunoblotting. mRNA expressions were detected by qRT-PCR. Cell proliferation was assessed by CCK-8. Left atrial electroanatomical voltage maps were created using PentaRay catheters and a 3-dimensional mapping system. KEY FINDINGS: OPN was highly expressed in the circulation of AF patients and was further increased with the progression of AF. In addition, correlation analysis showed that circulating OPN positively related with low-voltage areas (LVAs, a marker of atrial fibrosis) in AF patients. Immunohistological staining and immunoblotting revealed an increased expression of OPN in AF patients who present a higher degree of atrial fibrosis. Furthermore, in vitro studies in cultured human atrial fibroblasts (hAFs) demonstrated that OPN promoted the proliferation of fibroblasts and increased production of collagen I and fibronectin. Mechanistically, the profibrotic effects of OPN on atrial fibroblasts were determined via activating Akt/GSK-3β/β-catenin signaling and suppressing autophagy. SIGNIFICANCE: This study uncovered a previously unrecognized profibrotic role of OPN in atrial fibrosis, which was achieved through activation of Akt/GSK-3β/β-catenin signaling pathway and suppression of autophagy, implying a promising therapeutic target in atrial fibrosis and AF.
AIMS: Atrial fibrosis is a common feature of atrial fibrillation (AF). Recently, it is reported that osteopontin (OPN) can induce fibrosis in lungs, livers and kidneys. However, its role in atrial fibrosis remains unclear. Here, we sought to determine the involvement of OPN in atrial fibrosis and the underlying mechanisms during this pathological remodeling process. MATERIALS AND METHODS: Protein expressions were determined by enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining and immunoblotting. mRNA expressions were detected by qRT-PCR. Cell proliferation was assessed by CCK-8. Left atrial electroanatomical voltage maps were created using PentaRay catheters and a 3-dimensional mapping system. KEY FINDINGS:OPN was highly expressed in the circulation of AFpatients and was further increased with the progression of AF. In addition, correlation analysis showed that circulating OPN positively related with low-voltage areas (LVAs, a marker of atrial fibrosis) in AFpatients. Immunohistological staining and immunoblotting revealed an increased expression of OPN in AFpatients who present a higher degree of atrial fibrosis. Furthermore, in vitro studies in cultured human atrial fibroblasts (hAFs) demonstrated that OPN promoted the proliferation of fibroblasts and increased production of collagen I and fibronectin. Mechanistically, the profibrotic effects of OPN on atrial fibroblasts were determined via activating Akt/GSK-3β/β-catenin signaling and suppressing autophagy. SIGNIFICANCE: This study uncovered a previously unrecognized profibrotic role of OPN in atrial fibrosis, which was achieved through activation of Akt/GSK-3β/β-catenin signaling pathway and suppression of autophagy, implying a promising therapeutic target in atrial fibrosis and AF.
Authors: Stephan R Künzel; Maximilian Hoffmann; Michael Wagner; Ali El-Armouche; Silvio Weber; Karolina Künzel; Susanne Kämmerer; Mario Günscht; Erik Klapproth; Johanna S E Rausch; Mirna S Sadek; Tomasz Kolanowski; Stefanie Meyer-Roxlau; Christopher Piorkowski; Sems M Tugtekin; Stefan Rose-John; Xiaoke Yin; Manuel Mayr; Jan Dominik Kuhlmann; Pauline Wimberger; Konrad Grützmann; Natalie Herzog; Jan-Heiner Küpper; Molly O'Reilly; S Nashitha Kabir; Laura C Sommerfeld; Kaomei Guan; Ben Wielockx; Larissa Fabritz; Stanley Nattel; Ursula Ravens; Dobromir Dobrev Journal: Circ Res Date: 2021-08-26 Impact factor: 17.367