Cx43 in mesenchymal stem cells promotes angiogenesis of the infarcted heart independent of gap junctions.
Mesenchymal stem cells (MSCs) with elevated levels of connexin 43 (Cx43) have been shown to exhibit improved protection for ischemic hearts. However, it remains unclear whether Cx43 is involved in the paracrine actions of angiogenesis, the major mechanism of cell therapy. In the present study, an in vitro model with deprivation of oxygen and a murine myocardial infarction model with permanent ligation of the left anterior‑descending (LAD) coronary artery were used to determine whether gap junctions in MSCs promote angiogenesis. It was observed that MSCs that overexpressed Cx43 (MSCs‑Cx43), improve the cardiac function of infarcted myocardium as compared with control MSCs (MSCs‑vector) and MSCs with Cx43 knocked down by small interfering RNA (MSCs‑siCx43), accompanied with a reduction of infarct size and an increase in the vascular density and maturity. Increased levels of representative angiogenic factors [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)] were produced by MSCs‑Cx43 compared with MSCs‑siCx43 in vivo and in vitro. However, neither Cx43 formed gap junction specific inhibitor (Cx43 mimetic peptide) or gap junction opener (antiarrhythmic peptide) affected the production of VEGF and bFGF in MSCs under hypoxic stress. These data support the hypothesis that Cx43 in MSCs promotes angiogenesis in the infarcted heart, independent of gap junction formation.
Department of Gerontology, The Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China.
De-Guo
DG
Wang
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Feng-Xiang
FX
Zhang
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Ming-Long
ML
Chen
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Hong-Jun
HJ
Zhu
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Bing
B
Yang
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
Ke-Jiang
KJ
Cao
D000818:Animals; D018031:Connexin 43 / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D006334:Heart Function Tests; D006439:Hemodynamics; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D018919:Neovascularization, Physiologic; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D018031:Connexin 43; D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; D016222:Fibroblast Growth Factor 2