Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion.
OBJECTIVE
Recent studies suggested that erythropoietin (Epo) receptors (EpoR) are expressed not only in the hematopoietic lineage cells but also in the heart and that the administration of recombinant human Epo elicits protective effects in myocardial ischemia and reperfusion (I/R). We tested our hypothesis that endogenous Epo signals mediated by EpoR expressed in the non-hematopoietic lineage cells play a protective role against myocardial I/R injury.


METHODS
Transgene-rescued EpoR null mutant mice (RES), which express EpoR exclusively in the hematopoietic lineage cells, were subjected to 30 min left coronary artery occlusion followed by reperfusion.


RESULTS
Hematocrit, heart rate, blood pressure, heart weight, and echocardiographic parameters were comparable between wild-type mice (WT) and RES under the baseline condition. After 24 h of reperfusion, the infarct size in RES with I/R (RES/MI) was larger than that in WT/MI. Caspase-3 activity and number of TUNEL-positive cardiomyocytes in the ischemic area were increased in RES/MI compared with WT/MI. The extents of p38 and JNK phosphorylations in the ischemic area were significantly increased in WT/MI, but not in RES/MI as compared with corresponding sham-operated mice. Plasma Epo concentration in RES/MI did not differ from that in sham-operated RES, while that in WT/MI was peaked at 24 h post I/R. Additionally, left ventricular (LV) end-diastolic diameter was increased and LV fractional shortening tended to be reduced in the RES/MI compared with WT/MI at 21 days after I/R.


CONCLUSIONS
These results suggest that the endogenous Epo-EpoR system in the non-hematopoietic lineage cells plays an important protective role against myocardial I/R injury.
Tada
Hiroko
H
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
Kagaya
Yutaka
Y
Takeda
Morihiko
M
Ohta
Jun
J
Asaumi
Yasuhide
Y
Satoh
Kimio
K
Ito
Kenta
K
Karibe
Akihiko
A
Shirato
Kunio
K
Minegishi
Naoko
N
Shimokawa
Hiroaki
H
D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D015153:Blotting, Western; D004921:Erythropoietin / Q000097:blood / Q000502:physiology*; D006400:Hematocrit; D051379:Mice; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009929:Organ Size; D017467:Receptors, Erythropoietin / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction; D020257:Ventricular Remodeling
D017467:Receptors, Erythropoietin; D004921:Erythropoietin