The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload

The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-ma...

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Bibliographic Details
Published in:Scientific reports 2015-10, Vol.5 (1), p.15881-15881, Article 15881
Main Authors: Ikeda, Masataka, Ide, Tomomi, Fujino, Takeo, Matsuo, Yuka, Arai, Shinobu, Saku, Keita, Kakino, Takamori, Oga, Yasuhiro, Nishizaki, Akiko, Sunagawa, Kenji
Format: Article
Language:English
Subjects:
AKT protein
Animals
Arteriovenous Fistula - metabolism
Arteriovenous Fistula - pathology
Atrophy
Blood pressure
Echocardiography
Growth factors
Heart
Heart - physiopathology
Heart diseases
Hemodynamics - drug effects
Hypertrophy
Hypertrophy, Left Ventricular - metabolism
Hypertrophy, Left Ventricular - physiopathology
Integration
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Mice
Mice, Inbred C57BL
Myocardium - metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Rapamycin
Sirolimus - analogs & derivatives
Sirolimus - pharmacology
TOR protein
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - metabolism
Ubiquitination
Up-Regulation - drug effects
Ventricle
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Summary:The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end-diastolic pressure (LVEDP)-dependent manner, mTOR inhibition suppressed eccentric hypertrophy and induced cardiac atrophy even under VO. Notably, Akt was ubiquitinated and phosphorylated in response to VO, and blocking the recruitment of Akt to the membrane completely abolished mTOR activation. Various growth factors were upregulated during VO, suggesting that these might be involved in Akt-mTOR activation. Furthermore, the rate of eccentric hypertrophy progression was proportional to mTOR activity, which allowed accurate estimation of eccentric hypertrophy by time-integration of mTOR activity. These results suggested that the Akt-mTOR axis plays a pivotal role in eccentric hypertrophy, and mTOR activity quantitatively determines the rate of eccentric hypertrophy progression. As eccentric hypertrophy is an inherent system of the heart for regulating cardiac output and LVEDP, our findings provide a new mechanistic insight into the adaptive mechanism of the heart.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep15881