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Int J Cardiol. 2015 Apr 1;184:28-35. doi: 10.1016/j.ijcard.2015.01.088. Epub 2015 Jan 29.
Heart-specific overexpression of (pro)renin receptor induces atrial fibrillation in mice.
Lian H¹, Wang X², Wang J³, Liu N⁴, Zhang L⁴, Lu Y⁴, Yang Y⁵, Zhang L⁶.
¹Key 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.
²State 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.
³Emergency 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.
⁴Key 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.
⁵Emergency 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.
⁶Key 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.
 Abstract
BACKGROUND:
Atrial fibrillation (AF) is the most common cardiac arrhythmia, causing substantial cardiovascular morbidity and mortality. Therenin-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.
METHODS AND 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.
Copyright © 2015. Published by Elsevier Ireland Ltd.
KEYWORDS: (Pro)renin receptor [(p)RR]; Atrial fibrillation (AF); Electrocardiogram; Transgenic mouse
PMID: 25697868  DOI: 10.1016/j.ijcard.2015.01.088