Abstract
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.
Highlights
IntroductionEccentric hypertrophy increases cardiac output and makes it possible to maintain the net forward output in the presence of regurgitation, thereby lowering LVEDP and resolving pulmonary congestion[9]
These results suggested that the eccentric hypertrophy resulting from diastolic wall stress during volume overload (VO) is a physiological feedback system for regulating the LVEDP that buffers an excessive preload via left ventricle (LV) dilatation
Three major findings emerged from the analysis of the VO model at both the physiological and molecular levels: 1) mTOR, whose activity depends on diastolic wall stress, is a pivotal regulator of eccentric hypertrophy during VO; 2) Akt is a major mediator of mTOR activation upon mechanical stretch in diastole; Figure 5
Summary
Eccentric hypertrophy increases cardiac output and makes it possible to maintain the net forward output in the presence of regurgitation, thereby lowering LVEDP and resolving pulmonary congestion[9]. It appears that diastolic wall stress, as defined by LVEDP and LV geometry, triggers eccentric hypertrophy as a physiologically well-designed feedback system for regulating LVEDP. MTOR was shown to be involved in PO-induced hypertrophy and LV remodeling after myocardial infarction in mice[22,23] While these studies indicated that mTOR plays a key role in the physiology and pathology of the heart[24], the precise mechanism of mTOR regulation in the heart is still unknown. We demonstrated that the Akt-mTOR axis regulates eccentric hypertrophy during VO in response to diastolic wall stress and that the mTOR activity determines the rate of eccentric hypertrophy progression, by showing that the heart weight (HW) during VO can be accurately estimated by time integration of mTOR activity
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