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

Authors

Hongchang Guo, Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases
Ke Ma, Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases
Wenjing Hao, Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases
Yao Jiao, Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases
Ping Li, Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases
Jing Chen, Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases
Chen Xu, Beijing University of Chemical Technology
Fu-Jian Xu, Beijing University of Chemical Technology
Wayne Bond Lau, Thomas Jefferson UniversityFollow
Jie Du, Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases
Xin-Liang Ma, Thomas Jefferson UniversityFollow
Yulin Li, Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases

Document Type

Article

Publication Date

12-15-2020

Comments

This article is the authors’ final published version in Clinical and Translational Medicine, Volume 10, Issue 8, December 2020, Article number e242.

The published version is available at https://doi.org/10.1002/ctm2.242. Copyright © Guo et al.

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.

Recommended Citation

Guo, Hongchang; Ma, Ke; Hao, Wenjing; Jiao, Yao; Li, Ping; Chen, Jing; Xu, Chen; Xu, Fu-Jian; Lau, Wayne Bond; Du, Jie; Ma, Xin-Liang; and Li, Yulin, "mir15a/mir16-1 cluster and its novel targeting molecules negatively regulate cardiac hypertrophy." (2020). Department of Emergency Medicine Faculty Papers. Paper 143.
https://jdc.jefferson.edu/emfp/143

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

33377640

Language

English