Pre-miRNA Hsa-Let-7a-2: a Novel Intracellular Partner of Angiotensin II Type 2 Receptor Negatively Regulating its Signals

Xiaoyan Liu^1*, Zhenzhen Chen^2*, Shuangyue Li^2*, Ling Jin³, Xiao Cui², Changting Cui², Yue Deng², Qiannan Gao², Luyun Fan², Yaping Niu², Wenjie Wang², Chunmei Cui³, Jiuchang Zhong¹, Qinghua Cui^3✉, Bin Geng^2✉, Jun Cai^2✉

1. Department of Cardiology, Heart Center, Beijing Key Laboratory of Hypertension Research, Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
2. Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing 100037, China.
3. Department of Biomedical Informatics, School of Basic Medical Sciences, Center for Non-Coding RNA Medicine, Third Hospital, Peking University, Beijing 100191, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Jun Cai, Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China. Tel. & FAX: +8601088322161, Email: caijunorg; Bin Geng, Hypertension C More

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Citation:
Liu X, Chen Z, Li S, Jin L, Cui X, Cui C, Deng Y, Gao Q, Fan L, Niu Y, Wang W, Cui C, Zhong J, Cui Q, Geng B, Cai J. Pre-miRNA Hsa-Let-7a-2: a Novel Intracellular Partner of Angiotensin II Type 2 Receptor Negatively Regulating its Signals. Int J Biol Sci 2022; 18(8):3237-3250. doi:10.7150/ijbs.70455. Available from https://www.ijbs.com/v18p3237.htm

Abstract

G protein-coupled receptors (GPCRs) are the largest family of druggable targets, and their biological functions depend on different ligands and intracellular interactomes. Some microRNAs (miRNAs) bind as ligands to RNA-sensitive toll-like receptor 7 to regulate the inflammatory response, thereby contributing to the pathogenesis of cancer or neurodegeneration. It is unknown whether miRNAs bind to angiotensin II (Ang II) type 2 receptor (AGTR2), a critical protective GPCR in cardiovascular diseases, as ligands or intracellular interactomes. Here, screening for miRNAs that bind to AGTR2, we identified and confirmed that the pre-miRNA hsa-let-7a-2 non-competitively binds to the intracellular third loop of AGTR2. Functionally, intracellular hsa-let-7a-2 overexpression suppressed the Ang II-induced AGTR2 effects such as cAMP lowering, RhoA inhibition, and activation of Src homology 2 domain-containing protein-tyrosine phosphatase 1, whereas hsa-let-7a-2 knockdown enhanced these effects. Consistently, overexpressed hsa-let-7a-2 restrained the AGTR2-induced antiproliferation, antimigration, and proapoptosis of cells, and vasodilation of mesenteric arteries. Our findings demonstrated that hsa-let-7a-2 is a novel intracellular partner of AGTR2 that negatively regulates AGTR2-activated signals.

Keywords: pre-miRNA, hsa-let-7a-2, AGTR2