Emerging Role of mTOR Signaling-Related miRNAs in Cardiovascular Diseases.

Arun Samidurai,Rakesh C Kukreja,Anindita Das

doi:10.1155/2018/6141902

Arun Samidurai, Rakesh C Kukreja + Show 1 more

Open Access

https://doi.org/10.1155/2018/6141902

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Abstract

Mechanistic/mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase of the phosphoinositide 3-kinase- (PI3K-) related kinase family, elicits a vital role in diverse cellular processes, including cellular growth, proliferation, survival, protein synthesis, autophagy, and metabolism. In the cardiovascular system, the mTOR signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of both physiological and pathological processes. MicroRNAs (miRs), a class of short noncoding RNA, are an emerging intricate posttranscriptional modulator of critical gene expression for the development and maintenance of homeostasis across a wide array of tissues, including the cardiovascular system. Over the last decade, numerous studies have revealed an interplay between miRNAs and the mTOR signaling circuit in the different cardiovascular pathophysiology, like myocardial infarction, hypertrophy, fibrosis, heart failure, arrhythmia, inflammation, and atherosclerosis. In this review, we provide a comprehensive state of the current knowledge regarding the mechanisms of interactions between the mTOR signaling pathway and miRs. We have also highlighted the latest advances on mTOR-targeted therapy in clinical trials and the new perspective therapeutic strategies with mTOR-targeting miRs in cardiovascular diseases.

Highlights

Cardiovascular disease (CVD) is one of the leading cause of mortality and morbidity in the world and is a global pandemic threat to human health [1, 2]
MTOR inhibition with rapamycin promotes the survival of oxygen-deprived cardiomyocytes through activation of autophagy via inhibition of Ras homolog enriched in brain (Rheb) protein [175]. These results indicate that Rheb is a main regulator of mTORC1 during cardiomyocyte energy stress, and Rheb/mTORC1 inhibition promotes cell survival through activation of autophagy [175]
The overexpression of miR-494 suppressed the levels of proapoptotic proteins (PTEN, ROCK1, and CaMKIIδ) after I/R injury, which induced AKT signaling in concert, a critical survival pathway in the myocardium mediated through mTORC2 activation [233]

Summary

Introduction

Cardiovascular disease (CVD) is one of the leading cause of mortality and morbidity in the world and is a global pandemic threat to human health [1, 2]. RhoB, an important partner in AKT-mTOR pathway, is a direct target of miR-21, and silencing of RhoB impairs endothelial cell migration and tubulogenesis, providing a possible mechanism for miR-21 to inhibit angiogenesis after rapamycin treatment [208, 209]. The overexpression of miR-494 suppressed the levels of proapoptotic proteins (PTEN, ROCK1, and CaMKIIδ) after I/R injury, which induced AKT signaling in concert, a critical survival pathway in the myocardium mediated through mTORC2 activation [233]. AntimiR-214 blocked the phosphorylation of both AKT and PRAS40 and attenuated renal cell hypertrophy, suggesting that inactivation of both mTORC1 and C2 is beneficial [268] Consistent with this finding, studies using placental tissue from women with GDM demonstrated a robust activation of both mTORC1 and C2 as evident with the increased phosphorylation of AKT (S473), (4EBP1), and p70 S6 kinase (S6K) [269]. The exclusive interplay between lncRNA Plascr and mTOR in regulation mediated by miR-214 of cardiac hypertrophy is yet to be identified

Therapeutic Potential of miRNA and mTOR Inhibitors in CVD

Conclusion