Intracardiac injection of erythropoietin induces stem cell recruitment and improves cardiac functions in a rat myocardial infarction model.
Erythropoietin (EPO) protects the myocardium from ischaemic injury and promotes beneficial remodelling. We assessed the therapeutic efficacy of intracardiac EPO injection and EPO-mediated stem cell homing in a rat myocardial infarction (MI) model. Following MI, EPO (3000 U/kg) or saline was delivered by intracardiac injection. Compared to myocardial infarction control group (MIC), EPO significantly improved left ventricular function (n =11-14, P < 0.05) and decreased right ventricular wall stress (n = 8, P < 0.05) assessed by pressure-volume loops after 6 weeks. MI-EPO hearts exhibited smaller infarction size (20.1 +/- 1.1% versus 27.8 +/- 1.2%; n = 6-8, P < 0.001) and greater capillary density (338.5 +/- 14.7 versus 259.8 +/- 9.2 vessels per mm2; n = 6-8, P < 0.001) than MIC hearts. Direct EPO injection reduced post-MI myocardial apoptosis by approximately 41% (0.27 +/- 0.03% versus 0.42 +/- 0.03%; n = 6, P= 0.005). The chemoattractant SDF-1 was up-regulated significantly assessed by quantitative realtime PCR and immunohistology. c-Kit(+) and CD34(+) stem cells were significantly more numerous in MI-EPO than in MIC at 24 hrs in peripheral blood (n = 7, P < 0.05) and 48 hrs in the infarcted hearts (n = 6, P < 0.001). Further, the mRNAs of Akt, eNOS and EPO receptor were significantly enhanced in MI-EPO hearts (n = 7, P < 0.05). Intracardiac EPO injection restores myocardial functions following MI, which may attribute to the improved early recruitment of c-Kit(+) and CD34(+) stem cells via the enhanced expression of chemoattractant SDF-1.
Klopsch
Christian
C
Department of Cardiac Surgery, University of Rostock, Germany.
Furlani
Dario
D
Gäbel
Ralf
R
Li
Wenzhong
W
Pittermann
Erik
E
Ugurlucan
Murat
M
Kundt
Guenther
G
Zingler
Christiana
C
Titze
Ulf
U
Wang
Weiwei
W
Ong
Lee-Lee
LL
Wagner
Klaus
K
Li
Ren-Ke
RK
Ma
Nan
N
Steinhoff
Gustav
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D006334:Heart Function Tests; D006400:Hematocrit; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007267:Injections; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D020107:Troponin T / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D020107:Troponin T; D004921:Erythropoietin; D020778:Matrix Metalloproteinase 2