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

• Main 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
• Format: Article
• Language: English
• Published: Wiley 2020-12-01
• Series: Clinical and Translational Medicine
• Subjects: biomarkers; cardiac hypertrophy; heart failure; miRNAs; therapeutic target
• Online Access: https://doi.org/10.1002/ctm2.242

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.