Combined treatment with erythropoietin and granulocyte colony-stimulating factor enhances neovascularization and improves cardiac function after myocardial infarction.

Jingyi Xue; Guoqing DU; Jing Shi; Yue LI; Masahiro Yasutake; Lei Liu; Jianqiang LI; Yihui Kong; Shuxian Wang; Fengxiang Yun; Weimin LI

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Combined treatment with erythropoietin and granulocyte colony-stimulating factor enhances neovascularization and improves cardiac function after myocardial infarction.

Author: Jingyi XUE ¹ ; Guoqing DU ² ; Jing SHI ¹ ; Yue LI ¹ ; Masahiro YASUTAKE ³ ; Lei LIU ¹ ; Jianqiang LI ¹ ; Yihui KONG ¹ ; Shuxian WANG ¹ ; Fengxiang YUN ¹ ; Weimin LI ⁴
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1. Department of Cardiology, the First Clinical Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, China.
2. Department of Ultrasound, the Second Clinical Hospital, Harbin Medical University, Harbin, Heilongjiang 150086 China.
3. Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
4. Department of Cardiology, the First Clinical Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, China. Email: xuejingyi72@163.com.
Publication Type:Journal Article
MeSH: Animals; Blotting, Western; Chemokine CXCL12; metabolism; Echocardiography; Erythropoietin; therapeutic use; Flow Cytometry; Granulocyte Colony-Stimulating Factor; therapeutic use; Male; Myocardial Infarction; drug therapy; metabolism; Neovascularization, Physiologic; drug effects; Rats; Rats, Sprague-Dawley
From: Chinese Medical Journal 2014;127(9):1677-1683
CountryChina
Language:English
Abstract:
BACKGROUNDErythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are both potential novel therapeutics for use after myocardial infarction (MI). However, their underlying mechanisms remain unclear and the efficacy of monotherapy with EPO or G-CSF is also controversial. Therefore, we investigated the effects of combined treatment with EPO and G-CSF on neovascularization and cardiac function in post-infarction rats and explored the potential mechanisms.
METHODSFour groups of rats were used: control (saline injection after MI, i.h.), EPO (a single dose of 5 000 IU/kg after MI, i.h.), G-CSF (a dose of 50 µg× kg(-1)× d(-1) for 5 days after MI, i.h.), and both EPO and G-CSF (EPO+G-CSF, using the same regiment as above). Cardiac function was assessed by echocardiography before and 1 day, 7 days, 14 days and 21 days after MI. CD34(+)/Flk-1(+) cells in the peripheral blood were evaluated by flow cytometry before and 3 days, 5 days and 7 days after MI. The infarct area and angiogenesis in the peri-infarct area were analyzed. The mRNA and protein expression of vascular endothelial growth factor (VEGF) and stromal-derived factor-1a (SDF-1α) in the peri-infarct area were detected by real-time quantitative RT-PCR and Western blotting.
RESULTSCompared with the control and monotherapy groups, the EPO+G-CSF group had significantly increased CD34(+)/Flk-1(+) endothelial progenitor cells (EPCs) in the peripheral blood (P < 0.05), up-regulated VEGF and SDF-1α levels in the peri-infarct region (P < 0.05), enhanced capillary density (P < 0.05), reduced infarct size (P < 0.05) and improved cardiac structure and function (P < 0.05). G-CSF alone did not dramatically increase EPCs in the peripheral blood, enhance capillary density in the peri-infarct area or reduce infarct size compared with the control group.
CONCLUSIONSCombined treatment with EPO and G-CSF increased EPCs mobilization, up-regulated VEGF and SDF-1α levels in the post-infarction microenvironment, subsequently enhanced neovascularization in the peri-infarct region and reduced infarct size. All factors contributed to its beneficial effects on cardiac function in post-infarction rats.