PMID- 23747752
OWN - NLM
STAT- MEDLINE
DCOM- 20131017
LR  - 20191210
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 310
DP  - 2013 Aug 9
TI  - Roles of 3,4-methylenedioxymethamphetamine (MDMA)-induced alteration of 
      connexin43 and intracellular Ca(2+) oscillation in its cardiotoxicity.
PG  - 61-72
LID - S0300-483X(13)00143-1 [pii]
LID - 10.1016/j.tox.2013.05.013 [doi]
AB  - Although it is well known that 3,4-methylenedioxymethamphetamine (MDMA) can cause 
      various cardiovascular abnormalities and even sudden death from cardiac 
      arrhythmia, whether it has any effect on myocardial gap junctions, which might be 
      one of the targets mediating MDMA-induced cardiotoxicity, remains unclear. 
      OBJECTIVE: To test the hypothesis that MDMA may affect the myocardial gap 
      junction protein connexin43 (Cx43) and induce cardiac dysrhythmia. METHOD: (1) In 
      vivo study: adult rats were treated with a single dose MDMA administration 
      (20mg/kg, i.p.). Electrocardiogram detection and immunohistochemical analysis 
      were performed to evaluate cardiac function and expression of Cx43, respectively; 
      (2) in vitro study: cultured ventricular myocytes of neonatal rats were treated 
      with MDMA (10, 100, 1000mumol/L) for 1h. Western blotting and real-time 
      quantitative polymerase chain reaction (RT-qPCR) were performed to investigate 
      the total Cx43 mRNA expression. Immunofluorescent analysis was used to evaluate 
      the amount of junctional Cx43. The phosphorylation status of Cx43 at site Ser368 
      and intracellular Ca(2+) oscillation were also studied. RESULTS: Obvious changes 
      in electrocardiographic patterns were found in rats following MDMA 
      administration. They were characterized by prolonged QRS duration associated with 
      increased amplitude of QRS complex. The heart rates in treated rats were 
      significantly decreased compared to the rats in the control group. The 
      immunohistochemical findings revealed a significant decrease in Cx43 expression. 
      The in vitro study also showed a marked decline in total Cx43 protein associated 
      with reduction of Cx43 mRNA, whereas the phosphorylated Cx43 at Ser368 was 
      increased. Decrease of junctional Cx43 was found correlated with reduction in 
      N-cadherin induced by high concentration of MDMA. Additionally, confocal 
      microscopy findings revealed alteration of intracellular calcium oscillation 
      patterns characterized by high frequency and increasing influx Ca(2+). 
      CONCLUSIONS: MDMA reduces expression of cardiac gap junction protein Cx43. The 
      increase of phosphorylation status of Cx43 at Ser368 induced by MDMA is 
      attributed, at least in part, to the Ca(2+)-dependent regulation of protein 
      kinase C (PKC) activity. Our findings provide first evidence of MDMA-mediated 
      changes in those cardiac gap junctions that may underlie MDMA-induced cardiac 
      arrhythmia.
CI  - Copyright (c) 2013 Elsevier Ireland Ltd. All rights reserved.
FAU - Zhuo, Luo
AU  - Zhuo L
AD  - Department of Forensic Medicine, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan, Hubei 430030, China.
FAU - Liu, Quan
AU  - Liu Q
FAU - Liu, Liang
AU  - Liu L
FAU - Sun, Ting-yi
AU  - Sun TY
FAU - Wang, Rong-shuai
AU  - Wang RS
FAU - Qu, Guo-qiang
AU  - Qu GQ
FAU - Liu, Qian
AU  - Liu Q
FAU - Liu, Yan
AU  - Liu Y
FAU - Ren, Liang
AU  - Ren L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130606
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Connexin 43)
RN  - 0 (Illicit Drugs)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Arrhythmias, Cardiac/chemically induced/*metabolism
MH  - Blotting, Western
MH  - Calcium/*metabolism
MH  - Cell Culture Techniques
MH  - Cells, Cultured
MH  - Connexin 43/*biosynthesis/genetics
MH  - Electrocardiography
MH  - Gap Junctions/drug effects/metabolism
MH  - Gene Expression/drug effects
MH  - Illicit Drugs/*toxicity
MH  - Immunohistochemistry
MH  - Male
MH  - Microscopy, Fluorescence
MH  - Myocardium/*metabolism
MH  - Myocytes, Cardiac/drug effects/metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Real-Time Polymerase Chain Reaction
OTO - NOTNLM
OT  - 3,4-Methylenedioxymethamphetamine
OT  - Calcium oscillation
OT  - Connexins43
OT  - N-cadherin
OT  - Phosphorylation
EDAT- 2013/06/12 06:00
MHDA- 2013/10/18 06:00
CRDT- 2013/06/11 06:00
PHST- 2013/04/15 00:00 [received]
PHST- 2013/05/16 00:00 [revised]
PHST- 2013/05/28 00:00 [accepted]
PHST- 2013/06/11 06:00 [entrez]
PHST- 2013/06/12 06:00 [pubmed]
PHST- 2013/10/18 06:00 [medline]
AID - S0300-483X(13)00143-1 [pii]
AID - 10.1016/j.tox.2013.05.013 [doi]
PST - ppublish
SO  - Toxicology. 2013 Aug 9;310:61-72. doi: 10.1016/j.tox.2013.05.013. Epub 2013 Jun 
      6.