Wang Li-Ping, Yang Xiu-Hong, Wang Xiao-Jun, Li Shu-Min, Sun Na, Zhang Tian
Department of Physiology and Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Science, North China University of Science and Technology, Tangshan, China.
Cardiology. 2016;133(2):97-108. doi: 10.1159/000440995. Epub 2015 Oct 30.
The aim of this study was to investigate the protective role of erythropoietin (EPO) against myocardial fibrosis (MF).
Pressure-overloaded rats were established by abdominal aortic constriction, the rats were randomly divided in a double-blind manner into 3 groups (n = 12 for each group): sham-operated rats (sham), operated rats receiving physiological saline (vehicle) and operated rats receiving 4,000 U/kg rhEPO (EPO group). The vehicle and drugs were administered to rats by intraperitoneal injection. In addition, cultured adult rat cardiac fibroblasts (CFs) were utilized to investigate the role of EPO in CF proliferation and collagen secretion.
After 4 weeks, besides an increase in blood pressure, myocardial hypertrophy, collagen deposition in the myocardium and decreased cardiac function were observed in the pressure-overloaded rats. The expression of NADPH oxidase (Nox2 and Nox4) and inflammatory cytokines (CD45, F4/80 and MCP-1) was also significantly increased. All these alterations were prevented by EPO. TGF-β promoted CF proliferation, collagen secretion, ROS production and Nox2/Nox4 expression, which was inhibited by EPO. In addition, the TGF-β-induced increase of ERK1/2 phosphorylation and NF-x03BA;B expression were attenuated by EPO.
EPO inhibited rat MF induced by pressure overload and improved myocardial function by decreasing CF proliferation and differentiation via inhibition of the NADPH-ERK-NF-x03BA;B pathway.
本研究旨在探讨促红细胞生成素（EPO）对心肌纤维化（MF）的保护作用。
通过腹主动脉缩窄建立压力超负荷大鼠模型，将大鼠以双盲方式随机分为3组（每组n = 12）：假手术大鼠（假手术组）、接受生理盐水的手术大鼠（载体组）和接受4000 U/kg重组人促红细胞生成素的手术大鼠（EPO组）。通过腹腔注射向大鼠给药载体和药物。此外，利用培养的成年大鼠心脏成纤维细胞（CFs）研究EPO在CF增殖和胶原分泌中的作用。
4周后，除血压升高外，压力超负荷大鼠出现心肌肥大、心肌胶原沉积及心功能下降。烟酰胺腺嘌呤二核苷酸磷酸氧化酶（Nox2和Nox4）和炎性细胞因子（CD45、F4/80和单核细胞趋化蛋白-1）的表达也显著增加。所有这些改变均被EPO阻止。转化生长因子-β（TGF-β）促进CF增殖、胶原分泌、活性氧生成及Nox2/Nox4表达，而EPO可抑制这些作用。此外，EPO减弱了TGF-β诱导的细胞外信号调节激酶1/2（ERK1/2）磷酸化增加及核因子κB（NF-κB）表达。
EPO通过抑制NADPH-ERK-NF-κB信号通路，减少CF增殖和分化，从而抑制压力超负荷诱导的大鼠MF并改善心功能。
