Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion

doi:10.1016/j.cardiores.2006.05.010

Cardiovascular Research 2006 71(3):466-477; doi:10.1016/j.cardiores.2006.05.010

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Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion

Hiroko Tada^a, Yutaka Kagaya^a^,*, Morihiko Takeda^a, Jun Ohta^a, Yasuhide Asaumi^a, Kimio Satoh^a, Kenta Ito^a, Akihiko Karibe^a, Kunio Shirato^a, Naoko Minegishi^b and Hiroaki Shimokawa^a

^aDepartment of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
^bTohoku University Biomedical Engineering Research Organization, Sendai, Japan

^* Corresponding author. Tel.: +81 22 717 7153, fax: +81 22 717 7156. Email address: kagaya{at}cardio.med.tohoku.ac.jp

Objective: Recent studies suggested that erythropoietin (Epo)receptors (EpoR) are expressed not only in the hematopoieticlineage cells but also in the heart and that the administrationof recombinant human Epo elicits protective effects in myocardialischemia and reperfusion (I/R). We tested our hypothesis thatendogenous Epo signals mediated by EpoR expressed in the non-hematopoieticlineage cells play a protective role against myocardial I/Rinjury.

Methods Transgene-rescued EpoR null mutant mice (RES), whichexpress EpoR exclusively in the hematopoietic lineage cells,were subjected to 30 min left coronary artery occlusionfollowed by reperfusion.

Results: Hematocrit, heart rate, blood pressure, heart weight,and echocardiographic parameters were comparable between wild-typemice (WT) and RES under the baseline condition. After 24 hof reperfusion, the infarct size in RES with I/R (RES/MI) waslarger than that in WT/MI. Caspase-3 activity and number ofTUNEL-positive cardiomyocytes in the ischemic area were increasedin RES/MI compared with WT/MI. The extents of p38 and JNK phosphorylationsin the ischemic area were significantly increased in WT/MI,but not in RES/MI as compared with corresponding sham-operatedmice. Plasma Epo concentration in RES/MI did not differ fromthat in sham-operated RES, while that in WT/MI was peaked at24 h post I/R. Additionally, left ventricular (LV) end-diastolicdiameter was increased and LV fractional shortening tended tobe reduced in the RES/MI compared with WT/MI at 21 days afterI/R.

Conclusions: These results suggest that the endogenous Epo–EpoRsystem in the non-hematopoietic lineage cells plays an importantprotective role against myocardial I/R injury.

KEYWORDS Apoptosis; Cytokines; Ischemia; Remodeling; MAP kinase

Time for primary review 20 days

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