Abstract 853: Important Protective Role of Endogenous Erythropoietin/Erythropoietin-Receptor System Against Pressure-Overload-Induced Left Ventricular Dysfunction in Mice in Vivo.
Background: Recent studies have suggested that erythropoietin (Epo) receptors (EpoR) are expressed not only in the hematopoietic lineage but also in the heart and that the administration of Epo elicits cardioprotective effects on myocardial ischemia and reperfusion (I/R) injury. We have previously demonstrated that endogenous Epo/EpoR system plays an important protective role against myocardial I/R injury in humans as well as in mice. However, it is unknown whether the endogenous Epo/EpoR system in the non-hematopoietic cells plays a protective role in pressure-overload-induced cardiac dysfunction.
Methods and Results: Transgene-rescued EpoR null mutant mice (EpoR−/−-rescued) that express EpoR exclusively in the hematopoietic lineage cells and wild-type mice were subjected to transverse aortic constriction (TAC). Echocardiography at 1 week after TAC demonstrated that LV end-diastolic diameter was significantly increased by 23%, and the LV fractional shortening was significantly decreased by 47% in EpoR−/−-rescued compared with wild-type mice. At 1 week after TAC, LV weight/tibia length and lung weight/tibia length ratios were significantly increased in EpoR−/−-rescued compared with wild-type mice by 23% and 71%, respectively. Myocardial cross-sectional area in EpoR−/−-rescued at 1 week after TAC was also significantly larger than that in wild-type mice, although LV fibrotic area was similarly increased after TAC in the 2 strains. Northern blot analysis revealed that ANP expression was significantly increased and SERCA2 expression was significantly decreased at 1 week after TAC in EpoR−/−-rescued compared with wild-type mice. In Western blotting, p38MAPK and STAT3 phosphorylations at 5 hours and 1 week after TAC were significantly impaired in EpoR−/−-rescued compared with wild-type mice. Finally, survival at 1 week after TAC was significantly lower in the EpoR−/−-rescued than in the wild-type mice (69 vs. 90%, P<0.01). All the values described above were comparable in the 2 strains with sham operation.
Conclusions: These results suggest that the endogenous Epo/EpoR system in the non-hematopoietic cells plays an important protective role against pressure-overload-induced LV dysfunction in vivo.