MiR-208a in Cardiac Hypertrophy and Remodeling.

Xing-Huai Huang,Jun Liu,Jia-Lu Li,Si-Qi Li,Xin-Yue Li,Zhi-Han Jiao,Shu-Xia Wang,Jian Ding

doi:10.3389/fcvm.2021.773314

Xing-Huai Huang, Jun Liu + Show 6 more

Open Access

https://doi.org/10.3389/fcvm.2021.773314

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Abstract

Various stresses, including pressure overload and myocardial stretch, can trigger cardiac remodeling and result in heart diseases. The disorders are associated with high risk of morbidity and mortality and are among the major health problems in the world. MicroRNAs, a class of ~22nt-long small non-coding RNAs, have been found to participate in regulating heart development and function. One of them, miR-208a, a cardiac-specific microRNA, plays key role(s) in modulating gene expression in the heart, and is involved in a broad array of processes in cardiac pathogenesis. Genetic deletion or pharmacological inhibition of miR-208a in rodents attenuated stress-induced cardiac hypertrophy and remodeling. Transgenic expression of miR-208a in the heart was sufficient to cause hypertrophic growth of cardiomyocytes. miR-208a is also a key regulator of cardiac conduction system, either deletion or transgenic expression of miR-208a disturbed heart electrophysiology and could induce arrhythmias. In addition, miR-208a appeared to assist in regulating the expression of fast- and slow-twitch myofiber genes in the heart. Notably, this heart-specific miRNA could also modulate the “endocrine” function of cardiac muscle and govern the systemic energy homeostasis in the whole body. Despite of the critical roles, the underlying regulatory networks involving miR-208a are still elusive. Here, we summarize the progress made in understanding the function and mechanisms of this important miRNA in the heart, and propose several topics to be resolved as well as the hypothetical answers. We speculate that miR-208a may play diverse and even opposite roles by being involved in distinct molecular networks depending on the contexts. A deeper understanding of the precise mechanisms of its action under the conditions of cardiac homeostasis and diseases is needed. The clinical implications of miR-208a are also discussed.

Highlights

As shown in a study by Grueter et al [45], transgenic expression of Med13 resulted in upregulation of β-isoform of myosin heavy chain (β-myosin heavy chain (MHC)), which appears contradictory to the observation in miR-208a, Cardiac, Hypertrophy, Remodeling miR-208a−/− mice
As shown in the study by Ding et al, heartspecific inactivation of Trbp (TrbpcKO) in mice resulted in progressive cardiac remodeling, concurrent with a “slow-to-fast” shift in myofiber gene expression in the heart, downregulation of normal cardiac slow-twitch myofiber genes and increased expression of genes encoding fast-twitch contractile proteins [34]
Unlike skeletal muscle cells, appear not to undergo fast- and slow-twitch fiber-type speciation, the findings from the study by Ding et al [34], raised a question of whether the “slow-to-fast” shift in myofiber gene expression in Trbp mutant hearts is accompanied with a change(s) in metabolic pathways [55]

Summary

Introduction

We focus on a cardiac muscle-specific miRNA, miR-208a (miR-208), which plays key roles in regulating heart function and appears to be master organizer of cardiac remodeling to pathogenic stress. Expression of β-MHC in adult cardiac muscle is one of the hallmarks of hypertrophy, but appears to be a maladaptive response in the heart, since it can accelerate the pathogenic remodeling [26,27,28].

Results

Conclusion