title: Focal adhesion kinase mediates atrial fibrosis via the AKT/S6K signaling pathway in chronic atrial fibrillation patients with rheumatic mitral valve disease.
abstract: BACKGROUND
  Atrial fibrosis, as a hallmark of atrial structural remodeling, plays a critical role in the maintenance of chronic atrial fibrillation (AF), but the mechanisms responsible for atrial fibrosis are still uncertain. Fibrogenesis represents a complex process in which focal adhesion kinase (FAK) plays an important role. Therefore, we investigated the role of FAK-mediated signaling in atrial fibrosis in patients with chronic AF related to rheumatic mitral valve disease (RMVD).
  
  
  METHODS
  Atrial appendages were excised from 45 patients with RMVD and either chronic AF (n=25, AF >6 months) or sinus rhythm (n=20). Fibrosis was assessed by histology, and FAK and its two downstream pathways (AKT/S6K and ERK1/2) were evaluated by western blotting. We further evaluated the role of FAK in fibrogenesis by culturing neonatal rat cardiac fibroblasts to determine the importance of FAK-regulated signaling in cardiac myofibroblast differentiation induced by transforming growth factor-β1 (TGFβ1).
  
  
  RESULTS
  Our study revealed that FAK can regulate its downstream signaling to cause fibrosis in atrial tissue and activate isolated fibroblasts. Histology revealed a significant increase in atrial fibrosis in AF patients. The phosphorylation of FAK and its downstream AKT/S6K signaling was increased secondary to TGFβ1-induced high expression of α-SMA, a marker of myofibroblast activity. FAK and AKT inhibitors suppressed α-SMA expression in TGFβ1-induced fibroblasts. However, ERK1/2 signaling seemed to be unrelated to the fibrotic process in AF patients.
  
  
  CONCLUSIONS
  The FAK-mediated AKT/S6K signaling pathway participated in atrial fibrogenesis and this finding may contribute to the prevention of atrial fibrosis associated with chronic AF in patients with underlying cardiac disease.
authors: Cardiovascular Surgery Department, Fuwai Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100037, China.
authors: Peide
authors: P
authors: Zhang
authors: Wei
authors: W
authors: Wang
authors: Xin
authors: X
authors: Wang
authors: Xu
authors: X
authors: Wang
authors: Yunhu
authors: Y
authors: Song
authors: Jing
authors: J
authors: Zhang
authors: Hui
authors: H
authors: Zhao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020517:Atrial Appendage / Q000201:enzymology / Q000473:pathology; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000201:enzymology* / Q000453:epidemiology; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D005355:Fibrosis / Q000201:enzymology / Q000453:epidemiology / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008943:Mitral Valve / Q000201:enzymology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012214:Rheumatic Heart Disease / Q000175:diagnosis / Q000201:enzymology* / Q000453:epidemiology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases
keywords: AKT/S6K signaling; Atrial fibrosis; Chronic atrial fibrillation; Focal adhesion kinase; Rheumatic mitral valve disease