title: Heart-specific overexpression of (pro)renin receptor induces atrial fibrillation in mice.
abstract: BACKGROUND
  Atrial fibrillation (AF) is the most common cardiac arrhythmia, causing substantial cardiovascular morbidity and mortality. The renin-angiotensin system (RAS) has been shown to be involved in the pathophysiology of AF. The (pro)renin receptor [(p)RR] is the last identified member of RAS. However, the role of (p)RR in AF is still unknown.
  
  
  RESULTS
  Circulating levels of (p)RR were determined using an immunosorbent assay in 22 patients with AF (paroxysmal or persistent) and 22 healthy individuals. The plasma levels of (p)RR increased 3.6-fold in AF patients (P<0.001), indicating a relationship between (p)RR and AF. To investigate the role of (p)RR in the regulation of cardiac arrhythmia, we generated a transgenic mouse with overexpression of human (p)RR gene specifically in the heart. Electrocardiograms from (p)RR transgenic mice showed typical atrial flutter since 2 months, then spontaneously converted to atrial fibrillation by 10 months. The atria of the transgenic mice demonstrated significant dilation and fibrosis, and exhibited a high incidence of sudden death. Additionally, the genes of SERCA and HCN4, which are involved in the electrophysiology of AF, were significantly down-regulated and up-regulated respectively in transgenic mice atria. The phosphorylation of Erk1/2 significantly increased in the atria of the transgenic mice, and the activated Erk1/2 was found predominantly in cardiac fibroblasts, suggesting that the transgenic (p)RR gene may induce atrial fibrillation by activation of Erk1/2 in the cardiac fibroblasts of the atria.
  
  
  CONCLUSIONS
  (p)RR promotes atrial structural and electrical remodeling in vivo, which indicates that (p)RR plays an important role in the pathological development of AF.
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Lian
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Emergency and Intensive Care Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Emergency and Intensive Care Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, China. Electronic address: yymwin@gmail.com.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address: zhanglf@cnilas.org.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D012083:Renin / Q000096:biosynthesis*; D025262:Vacuolar Proton-Translocating ATPases / Q000096:biosynthesis*; D000093342:Prorenin Receptor
chemical_list: D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor
keywords: (Pro)renin receptor [(p)RR]; Atrial fibrillation (AF); Electrocardiogram; Transgenic mouse