期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 63, 期 -, 页码 14-25出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2013.06.008
关键词
Inosine; Adenosine; Arrhythmias; Embryo; Autocrine/paracrine; Nucleoside transporters
资金
- Swiss National Science Foundation [310030-127633]
- Swiss National Science Foundation (SNF) [310030_127633] Funding Source: Swiss National Science Foundation (SNF)
We previously established that exogenous adenosine (ADO) induces transient arrhythmias in the developing heart via the adenosine A1 receptor (A(1)AR) and downstream activation of NADPH oxidase/ERK and PLC/PKC pathways. Here, we investigated the mechanisms by which accumulation of endogenous ADO and its derived compound inosine (INO) in the interstitial compartment induce rhythm and conduction troubles. The validated model of the spontaneously beating heart obtained from 4-day-old chick embryos was used. Quantitative RT-PCR showed that enzymes involved in ADO and INO metabolism (CD39, CD73 and eADA) as well as equilibrative (ENT1, -3, -4) and concentrative (CNT3) nucleoside transporters were differentially expressed in atria, ventricle and outflow tract. Inactivation of ENTs by dipyridamole, 1) increased myocardial ADO level, 2) provoked atrial arrhythmias and atrio-ventricular blocks (AVB) in 70% of the hearts, 3) prolonged P wave and QT interval without altering contractility, and 4) increased ERK2 phosphorylation. Blockade of CD73-mediated phosphohydrolysis of AMP to ADO, MEK/ERK pathway inhibition or A(1)AR inhibition prevented these arrhythmias. Exposure to exogenous INO also caused atrial ectopy associated with AVB and ERK2 phosphorylation which were prevented by A(1)AR or A(2A)AR antagonists exclusively or by MEK/ERK inhibitor. Inhibition of ADA-mediated conversion of ADO to INO increased myocardial ADO and decreased INO as expected, but slightly augmented heart rate variability without provoking AVB. Thus, during cardiogenesis, disturbances of nucleosides metabolism and transport, can lead to interstitial accumulation of ADO and INO and provoke arrhythmias in an autocrine/paracrine manner through A(1)AR and A(2A)AR stimulation and ERK2 activation. (C) 2013 Elsevier Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据