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

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-molec...

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Bibliographic Details
Published in:Journal of biological engineering 2021-10, Vol.15 (1), p.1-24, Article 24
Main Authors: Cha, Byung-Hyun, Jung, Minjin, Kim, Angela S, Lepak, Victoria C, Colson, Brett A, Bull, David A, Won, Youngwook
Format: Article
Language:English
Subjects:
AKT protein
Antibodies
AZD2014
Cardiac hypertrophy
Cardiomyocyte
Cardiomyocytes
Cardiomyopathy
Gene expression
Health aspects
Heart
Heart enlargement
Hypertrophy
Inhibitors
Kinases
Milk
Morbidity
mTOR inhibitor
Muscle proteins
Myosin
Peptides
Phenotypes
Phenylephrine
Physiological aspects
Protein binding
Proteins
Rapamycin
Risk analysis
Risk factors
Signal transduction
TOR protein
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Summary: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.
ISSN:1754-1611
1754-1611
DOI:10.1186/s13036-021-00276-3