Protective role of endogenous erythropoietin system in nonhematopoietic cells against pressure overload-induced left ventricular dysfunction in mice
Protective role of endogenous erythropoietin system in nonhematopoietic cells against pressure overload-induced left ventricular dysfunction in mice
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DOI：
10.1161/circulationaha.106.659037
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发表时间：
2007-04-17
期刊：
影响因子：
37.8
通讯作者：
Shimokawa, Hiroaki
中科院分区：
文献类型：
--
作者：
Asaumi, Yasuhide;Kagaya, Yutaka;Shimokawa, Hiroaki
背景-促红细胞生成素(EPO)受体(EpoRs)在心脏表达。我们最近证实，内源性EPO-EPOR系统在小鼠和人类的心肌缺血中起着重要的保护作用。在本研究中，我们验证了我们的假设，即非造血细胞中的内源性EPO-EPOR系统也在体内对压力超负荷引起的心功能障碍起到保护作用。方法和结果-转基因拯救的EPOR缺失突变小鼠(EPOR(SAVEED)(-/-))仅在造血细胞中表达EPOR，并造成横动脉缩窄(TAC)。在TAC后1周，EPOR(救治)(-/-)小鼠的左心室重量和肺重量显著高于野生型小鼠，尽管TAC后这两种基因型鼠的纤维化面积均有增加。EPOR(获救)(-/-)组与野生型TAC组比较，左室舒张末期内径显著增加，左室短轴缩短率显著降低，存活率显著降低。野生型小鼠TAC后5小时和1周的STAT3和p38的磷酸化水平显著增加，而EPOR(-/-)小鼠则无明显变化。EPOR(救治)(-/-)TAC组小鼠左室心肌血管内皮生长因子蛋白表达和毛细血管密度较野生型TAC组小鼠显著降低。结论非造血细胞内源性EPO-EPOR系统对压力超负荷所致的在体心功能障碍具有重要的保护作用。
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.