Oscillating pressure treatment upregulates connexin43 expression in skeletal myoblasts and enhances therapeutic efficacy for myocardial infarction.
Transplantation of autologous skeletal myoblasts (SMBs) is a potential therapeutic approach for myocardial infarction. However, their clinical efficacy and safety is still controversial. Electrical coupling through gap junction between SMBs and host myocardium is essential for synchronized contraction and electrical stability. Here, we investigated the effect of heart beat-simulating environment, oscillating pressure, on the expression of connexin43 in two types of SMBs from rat and mouse. We found that connexin43 is markedly decreased under ischemia-mimicking conditions such as serum starvation and hypoxia (1% O(2)) in rat primary cultured SMBs and mouse C2C12 SMB cell line. Interestingly, the decrease of connexin43 expression under serum starvation was attenuated by oscillating pressure. Oscillating pressure treatment increased the expression of connexin43 twofold through AP-1 stimulation, which was blocked by PD98059, ERK inhibitor. In coculture of cardiomyocytes and C2C12, pressure-treated C2C12 and cardiomyocytes were able to form functional gap junction, which was demonstrated by both calcein-AM dye transfer assay and measurement of simultaneous contraction. In rat myocardial infarction model, transplantation of SMBs pretreated with oscillating pressure resulted in lesser ventricular dilatation and better systolic function than transplantation of untreated SMBs and control group. These results suggested that application of oscillating pressure on SMBs before transplantation may be useful to promote therapeutic efficacy for myocardial infarction by enhancing gap junction formation between transplanted and host cells.
Lee
Sae-Won
SW
National Research Laboratory for Cardiovascular Stem Cells and IRICT, Seoul National University Hospital, Seoul, Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
Kang
Hyun-Jae
HJ
Lee
Ji-Young
JY
Youn
Seock-Won
SW
Won
Joo-Yun
JY
Kim
Ji-Hyun
JH
Lee
Hyun-Chae
HC
Lee
Eun Ju
EJ
Oh
Se-il
SI
Oh
Byung-Hee
BH
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D017629:Gap Junctions / Q000502:physiology; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011312:Pressure; D051381:Rats; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
D018031:Connexin 43; D005419:Flavonoids; D018808:Transcription Factor AP-1; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one