Cytokine combination therapy with long-acting erythropoietin and granulocyte colony stimulating factor improves cardiac function but is not superior than monotherapy in a mouse model of acute myocardial infarction.
BACKGROUND
Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) are potential novel therapies after myocardial infarction (MI). We first established the optimal and clinically applicable dosages of these drugs in mobilizing hematopoietic stem cells (HSC), and then tested the efficacy of monotherapy and combination therapy post-MI.


RESULTS
Optimal doses were established in enhanced green fluorescent protein (eGFP) + chimeric mice (n = 30). Next, mice underwent MI and randomized into 4 groups (n = 18/group): 1) GCSF; 2) EPO; 3) EPO+GCSF; and 4) control. Left ventricular (LV) function was analyzed pre-MI, at 4 hours and at 28 days post-MI. Histological assessment of infarct size, blood vessels, apoptotic cardiomyocytes, and engraftment of eGFP+ mobilized cells were analyzed at day 28. LV function in the control group continued to deteriorate, whereas all treatments showed stabilization. The treatment groups resulted in less scarring, increased numbers of mobilized cells to the infarct border zone (BZ), and a reduction in the number of apoptotic cardiomyocytes. Both EPO groups had significantly more capillaries and arterioles at the BZ.


CONCLUSIONS
We have established the optimal doses for EPO and GCSF in mobilizing HSC from the bone marrow and demonstrated that therapy with these agents, either as monotherapy or combination therapy, led to improvement of cardiac function post-MI. Combination therapy does not seem to have additive benefit over monotherapy in this model.
Yeghiazarians
Yerem
Y
Division of Cardiology, Department of Medicine, University of California, San Francisco, San Francisco, California 94143-0103, USA. yeghiaza@medicine.ucsf.edu
Khan
Muhammad
M
Angeli
Franca S
FS
Zhang
Yan
Y
Jahn
Sarah
S
Prasad
Megha
M
Mirsky
Rachel
R
Shih
Henry
H
Minasi
Petros
P
Boyle
Andrew
A
Grossman
William
W
D000818:Animals; D016207:Cytokines / Q000008:administration & dosage; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000008:administration & dosage*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011828:Radiation Chimera; D011897:Random Allocation; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology*
D016207:Cytokines; D003692:Delayed-Action Preparations; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor