Activation of epidermal growth factor receptor mediates reperfusion arrhythmias in anaesthetized rats.
OBJECTIVE
Epidermal growth factor receptor (EGFR) plays a critical role in the development and function of the heart. Previous studies have demonstrated that EGFR is involved in regulating electrical excitability of the heart. The present study was designed to investigate whether EGFR activation would mediate cardiac arrhythmias induced by reperfusion in anaesthetized rats.


RESULTS
Reperfusion arrhythmias were induced by 10 min ligation of the left anterior descending coronary artery, followed by a 30 min reperfusion in anaesthetized rats. The incidence and severity of cardiac arrhythmias were significantly reduced by pre-treatment with the EGFR kinase inhibitor AG556. The phosphorylation level of myocardial EGFR was increased during ischaemia and at early reperfusion. Intramyocardial transfection of EGFR siRNA reduced EGFR mRNA and protein, and decreased the incidence of ventricular fibrillation induced by reperfusion. Interestingly, tyrosine phosphorylation levels of cardiac Na(+) channels (I(Na)) and L-type Ca(2+) channels (I(Ca,L)) were significantly increased at time points corresponding to the alteration of EGFR phosphorylation levels during reperfusion. AG556 pre-treatment countered the increased tyrosine phosphorylation level of Na(+) and L-type Ca(2+) channels induced by reperfusion. Patch-clamp studies proved that AG556 could inhibit I(Na) and I(Ca,L) in rat ventricular myocytes. No significant alteration was observed in tyrosine phosphorylation levels of cardiac Kv4.2 and Kir2.1 channels during reperfusion.


CONCLUSIONS
These results demonstrate for the first time that EGFR plays an important role in the genesis of arrhythmias induced by reperfusion, which is likely mediated at least in part by enhancing tyrosine phosphorylation of cardiac Na(+) and L-type Ca(2+) channels.
Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Mei
M
Feng
Ji-Zhou
JZ
Xiang
Zhang-Yin
ZY
Ming
Qin
Q
Fu
Rong
R
Ma
Qiu-Fang
QF
Zhang
Yao-Yan
YY
Dun
Lei
L
Yang
Hui
H
Liu
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000503:physiopathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015222:Sodium Channels; D020032:Tyrphostins; C098981:AG 556; C483803:Egfr protein, rat; D066246:ErbB Receptors