Theranostics 2021; 11(11):5404-5417. doi:10.7150/thno.48389 This issue Cite

Research Paper

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

Fangpu Yu1, Ya Zhang1, Zunzhe Wang1, Weigang Gong1, Cheng Zhang1,2✉

1. The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012 Jinan, China.
2. Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.

Citation:
Yu F, Zhang Y, Wang Z, Gong W, Zhang C. Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3. Theranostics 2021; 11(11):5404-5417. doi:10.7150/thno.48389. https://www.thno.org/v11p5404.htm
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Abstract

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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.

Keywords: circular RNA, eIF4A3, autophagy, atherosclerosis, coronary heart disease


Citation styles

APA
Yu, F., Zhang, Y., Wang, Z., Gong, W., Zhang, C. (2021). Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3. Theranostics, 11(11), 5404-5417. https://doi.org/10.7150/thno.48389.

ACS
Yu, F.; Zhang, Y.; Wang, Z.; Gong, W.; Zhang, C. Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3. Theranostics 2021, 11 (11), 5404-5417. DOI: 10.7150/thno.48389.

NLM
Yu F, Zhang Y, Wang Z, Gong W, Zhang C. Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3. Theranostics 2021; 11(11):5404-5417. doi:10.7150/thno.48389. https://www.thno.org/v11p5404.htm

CSE
Yu F, Zhang Y, Wang Z, Gong W, Zhang C. 2021. Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3. Theranostics. 11(11):5404-5417.

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