title: Erythropoietin administration after myocardial infarction in mice attenuates ischemic cardiomyopathy associated with enhanced homing of bone marrow-derived progenitor cells via the CXCR-4/SDF-1 axis.
abstract: Mobilization of bone marrow-derived stem cells (BMCs) was shown to have protective effects after myocardial infarction (MI). However, the classical mobilizing agent, granulocyte-colony stimulating factor (G-CSF) relapsed after revealing an impaired homing capacity. In the search for superior cytokines, erythropoietin (EPO) appears to be a promising agent. Therefore, we analyzed in a murine model of surgically induced MI the influence of EPO treatment on survival and functional parameters as well as BMC mobilization, homing, and effect on resident cardiac stem cells (CSCs). Human EPO was injected intraperitoneally after ligation of the left anterior descendens (LAD) for 3 days with a total dose of 5000 IU/kg 6 and 30 days after MI, and pressure volume relationships were investigated in vivo. Cardiac tissues were analyzed by histology. To show the effect on BMCs and CSCs, FACS analyses were performed. Homing factors were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA. EPO-treated animals showed a significant improvement of survival post-MI (62 vs. 36%). At days 6 and 30, all hemodynamic parameters associated with attenuated remodeling, enhanced neovascularization, and diminished apoptotic cells in the peri-infarct area were improved. BMC subpopulations (CD31(+), c-kit(+), and Sca-1(+) cells) were mobilized, and homing of Sca-1(+) and CXCR4(+) BMCs toward an SDF-1 gradient into the ischemic myocardium was enhanced. However, there was no beneficial effect on CSCs. We have shown that EPO application after MI shows cardioprotective effects. This may be explained by mobilization of BMCs, which are homing via the CXCR-4/SDF-1 axis. However, EPO has no beneficial effects on resident CSCs. Therefore, new treatment regimes using EPO together with other agents may combine complementary beneficial effects preventing ischemic cardiomyopathy.
authors.affiliation: Klinikum Grosshadern, Medical Department I, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brunner
authors.forename: Janina
authors.initials: J
authors.lastname: Winogradow
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Huber
authors.forename: Marc-Michael
authors.initials: MM
authors.lastname: Zaruba
authors.forename: Rebekka
authors.initials: R
authors.lastname: Fischer
authors.forename: Robert
authors.initials: R
authors.lastname: David
authors.forename: Gerald
authors.initials: G
authors.lastname: Assmann
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
authors.forename: Josef
authors.initials: J
authors.lastname: Mueller-Hoecker
authors.forename: Wolfgang-Michael
authors.initials: WM
authors.lastname: Franz
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology*; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015996:Survival Rate; D013997:Time Factors
chemical_list: D018952:Antigens, CD34; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D004921:Erythropoietin; D017493:Leukocyte Common Antigens