Rapid electrical stimulation of contraction modulates gap junction protein in neonatal rat cultured cardiomyocytes: involvement of mitogen-activated protein kinases and effects of angiotensin II-receptor antagonist.
OBJECTIVE
The aim of this study was to investigate the effects of rapid electrical stimulation (RES) of contraction on the expression of connexin (Cx)43 gap junction in neonatal rat cultured ventricular myocytes and the consequent changes of conduction properties.


BACKGROUND
The expression and distribution of gap junctions in cardiac muscle can be changed readily under a variety of pathological conditions because of dynamic turnover of Cxs. The effects of RES of contraction on gap junction remodeling are not well understood.


METHODS
Neonatal rat ventricular myocytes cultured for five days were subjected to RES (field stimulation) at 3.0 Hz for up to 120 min.


RESULTS
Rapid electrical stimulation resulted in a significant upregulation of Cx43 (by approximately 1.5-fold in protein and by approximately 1.9-fold in messenger ribonucleic acid at 60 min). Immunoreactive signal of Cx43 was also increased. Angiotensin II (AngII) content was increased significantly by RES >15 min. Phosphorylated forms of extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinases, and p38 mitogen-activated protein kinases (MAPKs) were all increased dramatically by RES with peaks at 5 - 60 min. Propagation of excitation was visualized by extracellular potential mapping by using a multiple electrode array system. Conduction velocity was increased significantly by RES for 60 to 90 min (25% - 27% increase). Treatment of myocytes with losartan (100 nmol/l) prevented most of these effects of RES; RES-induced upregulation of Cx43 was also prevented by specific inhibitors for ERK and p38 MAPKs.


CONCLUSIONS
A short-term RES causes upregulation of Cx43 in cardiomyocytes and a concomitant increase of conduction velocity, mainly through an autocrine action of AngII to activate ERK and p38 MAPKs.
Division of Cardiovascular Medicine, Department of Medical Bioregulation, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Noriko
N
Inoue
Tomoko
T
Ohkusa
Tomoko
T
Nao
Jong-Kook
JK
Lee
Tomo
T
Matsumoto
Yuji
Y
Hisamatsu
Takashi
T
Satoh
Masafumi
M
Yano
Kenji
K
Yasui
Itsuo
I
Kodama
Masunori
M
Matsuzaki
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D018031:Connexin 43 / Q000502:physiology; D004558:Electric Stimulation; D004586:Electrophoresis; D017629:Gap Junctions / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D012333:RNA, Messenger; D051381:Rats; D011945:Receptors, Angiotensin / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D018031:Connexin 43; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D020928:Mitogen-Activated Protein Kinases