Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3

Abstract

Rationale: Abnormal autophagic death of endothelial cells is detrimental to plaque structure as endothelial loss promotes lesional thrombosis. As emerging functional biomarkers, circular RNAs (circRNAs) are involved in various diseases, including cardiovascular. This study is aimed to determine the role of hsa_circ_0030042 in abnormal endothelial cell autophagy and plaque stability. Methods: circRNA sequencing and quantitative polymerase chain reaction were performed to detect hsa_circ_0030042 expression in coronary heart disease (CHD) and human umbilical vein endothelial cells (HUVECs). Transfection of stubRFP-sensGFP-LC3 adenovirus, flow cytometry, and electron microscopy were used to identify the role of hsa_circ_0030042 in ox-LDL‒induced abnormal autophagy in vitro. Bioinformatic analysis, RNA immunoprecipitation, immunofluorescence assay and other in vitro experiments were performed to elucidate the mechanism underlying hsa_circ_0030042-mediated regulation of autophagy. To evaluate the role of hsa_circ_0030042 in atherosclerotic plaques and endothelial function, we measured the carotid artery tension and performed histopathology and immunohistochemistry analysis. Results: hsa_circ_0030042 was significantly downregulated in CHD, while upon overexpression, it acted as an endogenous eukaryotic initiation factor 4A-III (eIF4A3) sponge to inhibit ox-LDL-induced abnormal autophagy of HUVECs and maintain plaque stability in vivo. Furthermore, hsa_circ_0030042 influenced autophagy by sponging eIF4A3 and blocking its recruitment to beclin1 and forkhead box O1 (FOXO1) mRNA, while hsa_circ_0030042-induced inhibition of beclin1 and FOXO1 was counteracted by eIF4A3 overexpression or decreased hsa_circ_0030042 binding. In high-fat-diet fed ApoE-/- mice, hsa_circ_0030042 also ameliorated plaque stability and counteracted eIF4A3-induced plaque instability. Conclusions: These results demonstrate a novel pathway involving hsa_circ_0030042, eIF4A3, FOXO1, and beclin1; hence, modulating their levels may be a potential therapeutic strategy against CHD.

CircRNA6783 Inhibits Cell Proliferation and Promotes Apoptosis in Lung Adenocarcinoma

“…Currently most reports are that they act as miRNA sponges to regulate gene expression. 23–27 For example, circSHKBP1 suppresses gastric cancer progression through serving as the sponge of oncogenic miR-582-3p to suppresses HSP90 degradation. 28 Circ-AASDH acts as a sponge for miR-140-3p regulates LUAD cells by inhibiting the proliferation and migration].…”

Hsa_circ_0004296 inhibits metastasis of prostate cancer by interacting with EIF4A3 to prevent nuclear export of ETS1 mRNA

“…Previous research showed that circSEMA5A increased the expression of host gene SEMA5A by recruiting EIF4A3 to enhance mRNA stability of SEMA5A, and thereby promoted BC angiogenesis [ 43 ]. Additionally, hsa_circ_0030042 promoted the cytoplasmic localization of EIF4A3 and inhibits FOXO1 and beclin1 expression by obstructing the interaction between EIF4A3 and their mRNAs [ 44 ]. Emerging studies have demonstrated that through direct interaction, circRNAs can modulate the nuclear localization of proteins as well as their corresponding biological functions.…”

Hsa_circ_0001879 promotes the progression of atherosclerosis by regulating the proliferation and migration of oxidation of low density lipoprotein (ox-LDL)-induced vascular endothelial cells via the miR-6873-5p-HDAC9 axis

“…CircRNAs play key roles in the progression of AS, especially in the function of endothelium vein cells. Hsa_circ_0030042 regulates autophagy and protects atherosclerotic plaque stability by targeting eIF4A3 [ 20 ]. The circular RNA circ_0003204 inhibits the proliferation, migration and tube formation of endothelial cells in atherosclerosis via the miR-370-3p/TGFβR2/phosph-SMAD3 axis [ 21 ].…”