Published Online
on April 2, 2007

A more recent version of this article appeared on April 17, 2007

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Submitted on August 17, 2006
Accepted on February 16, 2007

Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload-Induced Left Ventricular Dysfunction in Mice

Yasuhide Asaumi MD, Yutaka Kagaya MD^*, Morihiko Takeda MD, Nobuhiro Yamaguchi MD, Hiroko Tada MD, Kenta Ito MD, Jun Ohta MD, Takashi Shiroto MD, Kunio Shirato MD, Naoko Minegishi MD, and Hiroaki Shimokawa MD

From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine (Y.A., Y.K., M.T., N.Y., H.T., K.I., J.O., T.S., K.S., H.S.), and Biomedical Engineering Research Organization (N.M.), Tohoku University, Sendai, and Japan Science and Technology Agency, CREST, Tokyo (H.S.), Japan.

^* To whom correspondence should be addressed. E-mail: kagaya{at}cardio.med.tohoku.ac.jp.

Background--Erythropoietin (Epo) receptors (EpoRs) are expressed in the heart. We have recently demonstrated that the endogenous Epo-EpoR system plays an important protective role in myocardial ischemia in mice and humans. In the present study, we tested our hypothesis that the endogenous Epo-EpoR system in nonhematopoietic cells also plays a protective role against pressure overload-induced cardiac dysfunction in vivo.

Methods and Results--Transgene-rescued EpoR-null mutant mice (EpoR^-/-_rescued) that express EpoR exclusively in the hematopoietic cells were subjected to transverse aortic constriction (TAC). At 1 week after TAC, left ventricular weight and lung weight were significantly increased in EpoR^-/-_rescued mice compared with wild-type mice, although the fibrotic area was comparably increased after TAC in the 2 genotypes. In the EpoR^-/-_rescued mice with TAC, left ventricular end-diastolic diameter was significantly increased, left ventricular fractional shortening was significantly decreased, and survival rate was significantly decreased compared with wild-type mice with TAC. Phosphorylation of STAT3 at 5 hours and 1 week after TAC and that of p38 at 5 hours after TAC were significantly increased in wild-type mice but not in EpoR^-/-_rescued mice. Vascular endothelial growth factor protein expression and capillary density in left ventricular myocardium were significantly decreased in EpoR^-/-_rescued mice with TAC compared with wild-type mice with TAC.

Conclusions--These results suggest that the endogenous Epo-EpoR system in the nonhematopoietic cells plays an important protective role against pressure overload-induced cardiac dysfunction in vivo.

Key words: angiogenesis • erythropoietin • heart failure • hypertension • hypertrophy • remodeling

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