Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-κB Pathway

Abstract

Objectives: The aim of this study was to investigate the protective role of erythropoietin (EPO) against myocardial fibrosis (MF). Methods: 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. Results: 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-ß promoted CF proliferation, collagen secretion, ROS production and Nox2/Nox4 expression, which was inhibited by EPO. In addition, the TGF-ß-induced increase of ERK1/2 phosphorylation and NF-κB expression were attenuated by EPO. Conclusion: 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-κB pathway.

Regulation of TLR4 expression mediates the attenuating effect of erythropoietin on inflammation and myocardial fibrosis in rat heart

“…Downstream inflammatory mediators of the TLR4 signaling pathway, including TGF-β1 ( 30 ), TNF-α, IL-6 ( 31 ), IL-1β, IL-17A ( 32 ), MMP-9 and MMP-2 ( 33 ), promote the occurrence and development of MF ( 22 ). In the present study, it was demonstrated that EPO significantly decreased the release of TGF-β1, TNF-α, IL-6, IL-1β and IL-17A in serum and inhibited the expression of MMP-9 and MMP-2 in myocardial tissue of MF in rats subjected to AAC, which was consistent with the findings presented in other reports ( 11 , 34 , 35 ). The effects of EPO on inflammatory mediators may be key in attenuating MF.…”

“…In our preliminary study, EPO had significant anti-inflammatory effects and attenuated fibrosis in a pressure-overload rat model that was subjected to abdominal aortic constriction (AAC) ( 10 ). Furthermore, it has been indicated that EPO may be a powerful cardioprotective agent and a potential component for antifibrotic therapies ( 11 – 13 ). The protective mechanism may be via inhibiting the secretion of inflammatory factors, including transforming growth factor (TGF)-β, the interleukin (IL) family, and tumor necrosis factors (TNFs) ( 11 , 14 ).…”

“…Furthermore, it has been indicated that EPO may be a powerful cardioprotective agent and a potential component for antifibrotic therapies ( 11 – 13 ). The protective mechanism may be via inhibiting the secretion of inflammatory factors, including transforming growth factor (TGF)-β, the interleukin (IL) family, and tumor necrosis factors (TNFs) ( 11 , 14 ). However, the specific mechanism underlying the anti-inflammatory or antifibrotic activity of EPO in MF remains elusive.…”

The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization

“…EPO’s protective effect was described in a wide variety of processes in cardiovascular pathophysiology, particularly in ischaemia, cell proliferation, apoptosis, and platelet activation. EPO exhibited myocardial protection through the MAPK/ERK induced GATA-4 stability, reduction of caspase-3 activity, upregulation of Bcl-2 [ 94 ], and decreased myocardial fibrosis via suppressing the NADPH/ERK/NF-κB pathway [ 95 ]. Paracrine EPO accelerated the healing process in intramyocardial cardiac angiogenetic stem cells via the activation of AKT signaling and through the upregulation of upstream signals FOS and FZD7 in addition to the activation of TGF-β/WNT signaling [ 96 ].…”

Clinical Prescription-Protein-Small Molecule-Disease Strategy (CPSD), A New Strategy for Chinese Medicine Development: A Case Study in Cardiovascular Diseases

“…Besides, the Rho/Rho-associated coiled-coil forming protein kinase (ROCK)/ NF-kB signaling pathway can be inhibited by crocetin ester to exert a cardioprotective effect against AMI (Huang et al, 2016). By targeting the nicotinamide adenine dinucleotide phosphate (NADPH)/extracellular regulated protein kinase (ERK)/NF-kB pathway, erythropoietin can inhibit rat cardiac fibroblast proliferation, transformation, and collagen deposition (Wang et al, 2016). Receptor-interacting protein (RIP140), as well as inhibitor of NF-kB (IkB)/NF-kB p65 (p65)/IL-6, can be regulated by glycyrrhizic acid to preserve heart function by increasing cardiac antioxidants and reducing cardiomyocytes apoptosis (Yang et al, 2017a).…”