Downregulation of microRNA‐135b promotes atherosclerotic plaque stabilization in atherosclerotic mice by upregulating erythropoietin receptor

Abstract

Atherosclerotic plaque rupture is an important pathophysiologic mechanism of acute coronary syndrome. Emerging microRNAs (miRNAs) have been implicated in the atherosclerotic plaque formation and macrophage autophagy during the development of atherosclerosis (AS). Hence, this study was conducted to explore the role microRNA‐135b (miR‐135b) in macrophages and atherosclerotic plaque in mouse models of AS. The expression of miR‐135b and erythropoietin receptor (EPOR) was altered in atherosclerotic mice to clarify their effect on inflammation, cell activities of aortic tissues, and macrophage autophagy. The obtained findings unraveled that miR‐135b was upregulated and EPOR was downregulated in atherosclerotic mice. Upregulated miR‐135b expression promoted cell apoptosis and inflammation, along with inhibited cell proliferation and decreased macrophage autophagy. Notably, miR‐135 was validated to target EPOR and activate the PI3K/Akt signaling pathway. Moreover, miR‐135b inhibition attenuated inflammation, atherosclerotic plaque development, and promoted macrophage autophagy. Besides, the effect of miR‐135b inhibition was reversed in response to EPOR silencing. Taken conjointly, the study revealed that inhibition of miR‐135b promoted macrophage autophagy and atherosclerotic plaque stabilization in atherosclerotic mice by inactivating the PI3K/Akt signaling pathway and upregulating EPOR.

Role of PI3K in the Progression and Regression of Atherosclerosis

“…Reducing miR-155 (Zhai et al, 2014) andmiR-135b can effectively inhibit the PI3K/Akt/mTOR signaling pathways, enhance macrophage autophagy, and reduce plaque infiltration by macrophages, which in the early stage of atherosclerosis reduces the accumulation of foam cells and inhibits the formation and development of plaques (Wu et al, 2020). The latest findings indicate that the use of nanoparticles encapsulating chlorin e6-mediated photodynamic therapy (PDT) activates autophagy ( Figure 2) through the generation of ROS and inhibiting the PI3K/AKT/mTOR signaling pathways, and expression of proinflammatory factors in peritoneal M1 macrophages, thus reducing inflammation and increasing plaque stability (Han et al, 2019).…”

Long non‐coding RNA HULC protects against atherosclerosis via inhibition of PI3K/AKT signaling pathway

“…12 Conversely, a prior study has pointed out that blocking PI3K/AKT signaling pathway is donated to atherosclerotic plaque stabilization in AS. 11 Furthermore, the study has investigated that HULC lowers blood lipid levels and inhibits inflammatory and oxidative stress-related factor expression via inactivating PI3K/AKT signaling pathway in AS mice. There is a study identifying that inhibition of PI3K/AKT/ mammalian target of rapamycin complex 1 (mTORC1) signaling pathway activation partially ameliorates AS evidenced by reduced blood lipid levels and TC content.…”

“…Experimentally, activated PI3K/AKT signaling pathway is recognized to exacerbate atherosclerotic plaque formation and reduce the collagen content of atherosclerotic plaque 12 . Conversely, a prior study has pointed out that blocking PI3K/AKT signaling pathway is donated to atherosclerotic plaque stabilization in AS 11 . Furthermore, the study has investigated that HULC lowers blood lipid levels and inhibits inflammatory and oxidative stress‐related factor expression via inactivating PI3K/AKT signaling pathway in AS mice.…”

“…10 It is documented that inhibition of PI3K/AKT signaling pathway activation is donated to macrophage autophagy and atherosclerotic plaque stabilization in AS. 11 In addition, there is a study demonstrating that activation of PI3K/ AKT signaling pathway is partially responsible for the aggravation of AS injury. 12 The connection between HULC and PI3K/AKT signaling pathway has been indirectly described that HULC prevents MCL-1 from degradation while MCL-1 triggers PI3K/AKT signaling pathway activation.…”

“…The phosphatidylinositide 3‐kinase/protein kinase B (PI3K/AKT) signaling pathway serves as a pivotal role in macrophage survival, migration, and proliferation, which may affect the development of AS 10 . It is documented that inhibition of PI3K/AKT signaling pathway activation is donated to macrophage autophagy and atherosclerotic plaque stabilization in AS 11 . In addition, there is a study demonstrating that activation of PI3K/AKT signaling pathway is partially responsible for the aggravation of AS injury 12 .…”