The 3' Untranslated Region Protects the Heart from Angiotensin II-Induced Cardiac Dysfunction via AGGF1 Expression.

Autor:	Ding L; Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China., Lu S; Department of Pharmacology, University of California, Davis, Davis, CA, USA., Zhou Y; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China., Lyu D; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China., Ouyang C; Department of Pharmacy, Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437100, China., Ma Z; NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300134, China., Lu Q; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China. Electronic address: qiulunlu@njmu.edu.cn.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2020 Apr 08; Vol. 28 (4), pp. 1119-1132. Date of Electronic Publication: 2020 Feb 05.
DOI:	10.1016/j.ymthe.2020.02.002
Abstrakt:	The messenger RNA (mRNA) 3' untranslated regions (3' UTRs), as cis-regulated elements bound by microRNAs (miRNAs), affect their gene translation. However, the role of the trans-regulation of 3' UTRs during heart dysfunction remains elusive. Compared with administration of angiogenic factor with G-patch and forkhead-associate domains 1 (Aggf1), ectopic expression of Aggf1 with its 3' UTR significantly suppressed cardiac dysfunction in angiotensin II-infused mice, with upregulated expression of both Aggf1 and myeloid cell leukemia 1 (Mcl1). Along their 3' UTRs, Mcl1 and Aggf1 mRNAs share binding sites for the same miRNAs, including miR-105, miR-101, and miR-93. We demonstrated that the protein-coding Mcl1 and Aggf1 mRNAs communicate and co-regulate each other's expression through competition for these three miRNAs that target both transcripts via their 3' UTRs. Our results indicate that Aggf1 3' UTR, as a trans-regulatory element, accelerates the cardioprotective role of Aggf1 in response to hypertensive conditions by elevating Mcl1 expression. Our work broadens the scope of gene therapy targets and provides a new insight into gene therapy strategies involving 3' UTRs. (Copyright © 2020. Published by Elsevier Inc.)
Databáze:	MEDLINE
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