mir15a/mir16-1 cluster and its novel targeting molecules negatively regulate cardiac hypertrophy.

Authors

• Hongchang Guo
• Ke Ma
• Wenjing Hao
• Yao Jiao
• Ping Li
• Jing Chen
• Chen Xu
• Fu-Jian Xu
• Wayne Bond Lau
• Jie Du
• Xin-Liang Ma
• Yulin Li

Publication/Presentation Date

12-1-2020

Abstract

In response to pathological stimuli, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. miRNAs are increasingly recognized as pathogenic factors, clinically relevant biomarkers, and potential therapeutic targets. We identified that mir15a/mir16-1 cluster was negatively correlated with hypertrophic severity in patients with hypertrophic cardiomyopathy. The mir15a/mir16-1 expression was enriched in cardiomyocytes (CMs), decreased in hypertrophic human hearts, and decreased in mouse hearts after transverse aortic constriction (TAC). CM-specific mir15a/mir16-1 knockout promoted cardiac hypertrophy and dysfunction after TAC. CCAAT/enhancer binding protein (C/EBP)β was responsible for the downregulation of mir15a/mir16-1 cluster transcription. Mechanistically, mir15a/mir16-1 cluster attenuated the insulin/IGF1 signal transduction cascade by inhibiting multiple targets, including INSR, IGF-1R, AKT3, and serum/glucocorticoid regulated kinase 1 (SGK1). Pro-hypertrophic response induced by mir15a/mir16-1 inhibition was abolished by knockdown of insulin receptor (INSR), insulin like growth factor 1 receptor (IGF1R), AKT3, or SGK1. In vivo systemic delivery of mir15a/mir16-1 by nanoparticles inhibited the hypertrophic phenotype induced by TAC. Importantly, decreased serum mir15a/mir16-1 levels predicted the occurrence of left ventricular hypertrophy in a cohort of patients with hypertension. Therefore, mir15a/mir16-1 cluster is a promising therapeutic target and biomarker for cardiac hypertrophy.

Volume

10

Issue

8

First Page

242

Last Page

242

ISSN

2001-1326

Published In/Presented At

Guo, H., Ma, K., Hao, W., Jiao, Y., Li, P., Chen, J., Xu, C., Xu, F. J., Lau, W. B., Du, J., Ma, X. L., & Li, Y. (2020). mir15a/mir16-1 cluster and its novel targeting molecules negatively regulate cardiac hypertrophy. Clinical and translational medicine, 10(8), e242. https://doi.org/10.1002/ctm2.242

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

33377640

Department(s)

Administration and Leadership

Document Type

Article