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Relaxin activates AMPK-AKT signaling and increases glucose uptake by cultured cardiomyocytes

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Abstract

Purpose

Many evidences show that the hormone relaxin plays a pivotal role in the physiology and pathology of the cardiovascular system. This pleiotropic hormone exerts regulatory functions through specific receptors in cardiovascular tissues: in experimental animal models it was shown to induce coronary vasodilation, prevent cardiac damage induced by ischemia/reperfusion and revert cardiac hypertrophy and fibrosis. A tight relationship between this hormone and important metabolic pathways has been suggested, but it is at present unknown if relaxin could regulate cardiac metabolism. Our aim was to study the possible effects of relaxin on cardiomyocyte metabolism.

Methods

Neonatal rat cardiomyocytes were treated with relaxin and (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assays (MTT) were performed to assess metabolic activity; while 2-deoxy-D-[3H] glucose and BODIPY-labelled fatty acid incorporations were analyzed to measure glucose and fatty acid uptakes, and western blot was utilized to study the intracellular signaling pathways activated by the hormone.

Results

We observed that relaxin at 10 ng/ml was able to increase the level of metabolic activity of cultured neonatal rat cardiomyocytes; the rate of 2-deoxy-D-[3H]glucose incorporation demonstrated that relaxin also induced an increase in glucose uptake. First evidence is also offered that relaxin can activate the master energy sensor and regulator AMPK in cardiomyocytes. Moreover, the treatment of cardiomyocytes with relaxin also induced dose-dependent increases in ERK1/2, AKT, and AS160 phosphorylation. That raise in AS160 phosphorylation induced by relaxin was prevented by the pretreatment with AMPK and AKT pathways inhibitors, indicating that both molecules play important roles in the relaxin effects reported.

Conclusion

Relaxin can regulate cardiomyocyte metabolism and activate AMPK, the central sensor of energy status that maintains cellular energy homeostasis, and also ERK and AKT, two molecular sensing nodes that coordinate dynamic responses of the cell’s metabolic responses.

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Funding

This work was supported by the National Institute of Health “Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III” Madrid, Spain [PI15/00681 and CIBER de Enfermedades Cardiovasculares (CIBERCV)]; and European Regional Development Fund (FEDER). Alana Aragón-Herrera was funded by a predoctoral research grant from the Institute of Biomedical Research (IDIS-SERGAS), Xunta de Galicia, Santiago de Compostela, Spain, and by the FPU Program from the Spanish Ministry of Education, Culture and Sports.

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    Authors and Affiliations

    1. Cellular and Molecular Cardiology Unit and Department of Cardiology, Institute of Biomedical Research (IDIS-SERGAS), Santiago de Compostela, Spain

      A. Aragón-Herrera, S. Feijóo-Bandín, D. Rodríguez-Penas, J. R. González-Juanatey & F. Lago

    2. CIBERCV, Institute of Health Carlos III, Madrid, Spain

      S. Feijóo-Bandín, E. Roselló-Lletí, M. Portolés, M. Rivera, J. R. González-Juanatey & F. Lago

    3. Cardiocirculatory Unit, Health Institute of La Fe University Hospital (IIS La Fe), Valencia, Spain

      E. Roselló-Lletí, M. Portolés & M. Rivera

    4. Prosperius Institute, Florence, Italy

      M. Bigazzi & D. Bani

    5. Neuroendocrine Interaccions in Rheumatology and Inflammatory Diseases Unit, Institute of Biomedical Research (IDIS-SERGAS), Santiago de Compostela, Spain

      O. Gualillo

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    1. A. Aragón-Herrera
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    Aragón-Herrera, A., Feijóo-Bandín, S., Rodríguez-Penas, D. et al. Relaxin activates AMPK-AKT signaling and increases glucose uptake by cultured cardiomyocytes. Endocrine 60, 103–111 (2018). https://doi.org/10.1007/s12020-018-1534-3

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