RESUMEN
The mechanism underlying the antiinflammatory or antifibrotic activity of erythropoietin (EPO) in myocardial fibrosis (MF) remains elusive. In the current study, abdominal aortic constriction (AAC) was performed on rats and EPO and/or Tolllike receptor (TLR)4 were overexpressed in rat hearts through intramyocardial administration of lentivirus expressing the EPO and TLR4 genes. Hematoxylin and eosin staining and Masson's trichrome staining were performed on tissue sections from rat hearts for histopathological examination. ELISA was used to determine the levels of inflammatory mediators in serum. Gene expression levels were determined by quantitative polymerase chain reaction analysis and protein expression levels were determined by western blot analysis and immunofluorescence staining. The results indicated that EPO overexpression improved MF in rat hearts, by inhibiting the release of transforming growth factor (TGF)ß1, tumor necrosis factor (TNF)α, interleukin (IL)6, IL1ß, IL17A, matrix metalloproteinase (MMP)9 and MMP2. Moreover, EPO overexpression suppressed the expression of TLR4, while promoting phosphoinositide 3kinase (PI3K) and phosphorylated AKT serine/threonine kinase 1 (Akt) expression levels. However, the beneficial effects of EPO were attenuated by overexpression of TLR4. In addition, inhibition of PI3K/Akt signaling activity by treatment with LY294002 markedly reversed the protective effect of EPO on the AACinduced MF. Taken together, the present study demonstrated that EPO may have a critical role against MF by activating PI3K/Akt signaling and by downregulating TLR4 expression, thereby inhibiting the release of TGFß1, TNFα, IL6, IL1ß, IL17A, MMP9 and MMP2. These findings suggest that the PI3K/Akt/TLR4 signaling pathway is associated with the antiinflammatory effects of EPO and may play a role in attenuating AACinduced MF.
