AZD2014, a dual mTOR inhibitor, attenuates cardiac hypertrophy in vitro and in vivo

Byung-Hyun Cha,Brett A Colson,David A Bull,Victoria C Lepak,Minjin Jung,Angela S Kim,Youngwook Won

doi:10.1186/s13036-021-00276-3

Byung-Hyun Cha, Brett A Colson + Show 5 more

Open Access

https://doi.org/10.1186/s13036-021-00276-3

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Abstract

Cardiac hypertrophy is one of the most common genetic heart disorders and considered a risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) pathway plays a key regulatory function in cardiovascular physiology and pathology in hypertrophy. AZD2014 is a small-molecule ATP competitive mTOR inhibitor working on both mTORC1 and mTORC2 complexes. Little is known about the therapeutic effects of AZD2014 in cardiac hypertrophy and its underlying mechanism. Here, AZD2014 is examined in in vitro model of phenylephrine (PE)-induced human cardiomyocyte hypertrophy and a myosin-binding protein-C (Mybpc3)-targeted knockout (KO) mouse model of cardiac hypertrophy. Our results demonstrate that cardiomyocytes treated with AZD2014 retain the normal phenotype and AZD2014 attenuates cardiac hypertrophy in the Mybpc3-KO mouse model through inhibition of dual mTORC1 and mTORC2, which in turn results in the down-regulation of the Akt/mTOR signaling pathway.

Highlights

Hypertrophic cardiomyopathy (HCM) is a genetic heart disorder with the occurrence rate of 0.2–0.5% [1, 2]
(See figure on previous page.) Fig. 2 Effects of AZD2014 on phenylephrine (PE)-induced cardiac hypertrophy. a The mRNA expression levels of cardiac hypertrophy marker atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in cardiomyocytes treated as indicated were determined by quantitative real-time polymerase chain reaction (qRT-PCR). #, p > 0.05; *, p < 0.05 vs. non-PE treated group. n = 3. b The protein expression levels of ANP in cardiomyocytes treated as indicated were determined by fluorescence activated cell sorting (FACS) (The gray shaded peak is the isotype control)
We examined the effect of AZD2014, a dual mTOR complex 1 (mTORC1)/2 inhibitor, on PE–induced hypertrophic cardiomyocytes and a Myosinbinding protein-C (Mybpc3)-KO mouse model of HCM

Summary

Introduction

Hypertrophic cardiomyopathy (HCM) is a genetic heart disorder with the occurrence rate of 0.2–0.5% [1, 2]. None of the available pharmacological agents have shown to prevent the process of cardiac hypertrophy and cure the disease [6, 7], with the possible exception of diltiazem [8] for treatment of HCM patients. The mammalian target of rapamycin (mTOR) pathway appears to be involved in the development of HCM and is considered a therapeutic target for this disease [9,10,11]. The Akt/mTOR pathway contributes significantly to the activation of mTORC1 during the development of cardiac hypertrophy [13], while mTORC2 is involved in the regulation of cell survival, growth, and proliferation in cardiomyocytes [14]. Genetic deletion of mTORC1/2 in a heart impairs the development of cardiac hypertrophy [15]. A new agent capable of blocking the dual mTORC1/2 would be an effective means to prevent or

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