Dyssynchronous pacing triggers endothelial-mesenchymal transition through heterogeneity of mechanical stretch in a canine model.
BACKGROUND
Endothelial-mesenchymal transition (EndMT) plays a pivotal role in cardiac fibrosis. However, it is unclear whether EndMT is involved in dyssynchronous heart failure (DHF).


RESULTS
Twelve dogs received 3-week rapid right ventricular pacing (RVP) to develop DHF and then were randomly divided into a RVP group (n=6; RVP for another 3 weeks) and a biventricular pacing (BiVP) group (n=6; BiVP for 3 weeks), and another 6 dogs were in the control group. Contractile function in BiVP group was a little better than that in RVP group (P<0.05), but significant heart failure remained in 2 groups. RVP induced more significant cardiac fibrosis and higher collagen 1A2 expression in the left ventricular lateral wall (late-contracting and high-stress) than that in the anterior wall, and for those in the BiVP group, it was much lower. CD31, S100A4, α-smooth muscle actin and collagen 1A2 were used to evaluate EndMT. EndMT levels, transforming growth factor-β (TGF-β)/snail signaling, collagen 1A2 and integrin β1 expression were much higher in the endothelial cells from the RVP lateral wall than that from BiVP. In this in vitro study, cyclic stretch could independently induce EndMT and enhance the pro-EndMT effect of TGF-β in HUVECs, which could be partly blocked by integrin β1 siRNA.


CONCLUSIONS
RVP-induced DHF could aggravate fibrosis due to regional heterogeneity of mechanical stress, and it was better in the BiVP group where mechanical stress-induced EndMT might play a pivotal role through the integrin β1 pathway.
Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou; Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China.
JingTing
J
Mai
QingSong
Q
Hu
Yong
Y
Xie
ShiCheng
S
Su
Qiong
Q
Qiu
WoLiang
W
Yuan
Ying
Y
Yang
ErWei
E
Song
YangXin
Y
Chen
JingFeng
J
Wang
D000818:Animals; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D058406:Cardiac Resynchronization Therapy / Q000009:adverse effects; D054338:Cell Transdifferentiation / Q000502:physiology*; D024042:Collagen Type I / Q000096:biosynthesis; D004285:Dogs; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000473:pathology*; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008648:Mesoderm / Q000473:pathology*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011897:Random Allocation; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D024042:Collagen Type I; D019012:Integrin beta1; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta