DOI: 10.1161/circ.148.suppl_1.11896 ISSN: 0009-7322

Abstract 11896: Contribution of Amino Acid Transporter SLC7A5 to Pathological Ventricular Hypertrophy and Heart Failure

Javier Inserte, Sara Delgado, David Aluja, Elisabet Miro, Ignacio Ferreira, Jose A Barrabes
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: Transition from compensatory to pathological ventricular hypertrophy and heart failure (HF) is associated with metabolic remodeling. It has been described that hypoxia signaling induces the expression of the amino acid (AA) transporter SLC7A5 (LAT1) and the activation of its downstream pro-hypertrophic target mTORC1.

Hypothesis: Chronic pathologic stimuli induce AA metabolism reprogramming comprising increased AA transport through LAT1, which plays a key role in the development of hypertrophy and its progression to HF.

Methods: C57BL/6N mice were subjected to chronic pressure overload by constriction of the aorta (TAC). The selective LAT1 inhibitor JPH203 was chronically administered (ip) after TAC surgery. Dynamics of leucine were determined in heart samples from mice treated with 13C,15N-leucine using LC-MS/MS. Microarray-based gene expression profile, echocardiographic data, and markers of cardiac remodeling were measured at different time points.

Results: Microarray results showed a profound AA metabolism remodeling consisting of a general increase in the expression of AA transporters, with LAT1 as the most overexpressed and reduced expression of enzymes involved in BCAA catabolism. Overexpression of LAT1 was confirmed in isolated cardiomyocytes. These changes correlated with a marked increase in labeled leucine uptake with respect to sham mice (310%), a moderate reduction in the formation of its ketoacid (51% α-ketoisocaproate), and potent inhibition of its catabolism (21% isovalerate and 13% 3-hydroxy-3-methyl-glutarate), and enhanced activation of mTOR pathway. Administration of JPH203 reduced leucine transport and mTOR activation, partially reversed the inhibition of BCAA catabolism, and attenuated hypertrophy and cardiac dysfunction induced by TAC.

Conclusions: Pressure overload induces AA metabolic reprogramming characterized by enhanced AA transport and inhibited BCAA catabolism. LAT1 overexpression occurs in cardiomyocytes and contributes to adverse cardiac remodeling via mTOR pathway activation. We propose LAT1 inhibition as a novel therapeutic strategy against HF.

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