Erythropoietin promoted intraplaque angiogenesis by PI3K/AKT/mTOR signaling pathway in atherosclerosis

Abstract

Background: This study aimed to investigate role of erythropoietin in atherosclerosis and explore whether underlying mechanism is associated with PI3K/AKT/mTOR pathway.

Methods: High-fat-diet-induced atherosclerosis model was established in apolipoprotein E knockout mice (C57BL/6 genetic background). Mice were randomly divided into the control group and the EPO group. Hematoxylin-eosin was performed for the determination of atherosclerotic lesions. The expression levels of related proteins were detected by western blot analysis.

Results: Erythropoietin significantly enhanced the incidence of hemorrhage in atherosclerotic plaques compared with the control group. The proteins' expression signaling pathways (including PI3K, AKT, and mTOR) and angiogenesis-related proteins (VEGF, COX-2, and HIF-1α) were proved to be up-regulated by erythropoietin. Additionally, erythropoietin significantly enhanced the incidence of hemorrhage in the atherosclerotic plaques compared with the control group. The vitro experiments were conducted in macrophages at 21% O₂ or 1% O₂. The data showed that expression of p-PI3K, p-AKT, p-mTOR, VEGF, COX-2, and HIF-1α related proteins increased in 1% O₂ group than 21% O₂ group. Moreover, compared with control group, protein expression including p-PI3K, p-AKT, p-mTOR, VEGF, COX-2, and HIF-1α was markedly increased in EPO group, decreased in inhibitors group, and similar results were observed in EPO+ inhibitors group.

Conclusion: The present study demonstrated that erythropoietin might promote angiogenesis in atherosclerotic vulnerable by activating PI3K/AKT/mTOR signaling pathway in atherosclerotic, providing a novel therapeutic target for atherosclerotic targeted therapy.

Keywords: Angiogenesis; Atherosclerosis; Erythropoietin; PI3K/AKT/mTOR.