Angiotensin-(1–9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway

Cristian Sotomayor-Flores, Pablo Rivera-Mejías, César Vásquez-Trincado, Camila López-Crisosto, Pablo E. Morales, Christian Pennanen, Iva Polakovicova, Víctor Aliaga-Tobar, Lorena García, Juan Carlos Roa, Beverly A. Rothermel, Vinicius Maracaja-Coutinho, Hung Ho-Xuan, Gunter Meister, Mario Chiong, María Paz Ocaranza, Alejandro H. Corvalán, Valentina Parra, Sergio Lavandero

Research output: Contribution to journalArticle

Abstract

Angiotensin-(1–9) is a peptide from the noncanonical renin-angiotensin system with anti-hypertrophic effects in cardiomyocytes via an unknown mechanism. In the present study we aimed to elucidate it, basing us initially on previous work from our group and colleagues who proved a relationship between disturbances in mitochondrial morphology and calcium handling, associated with the setting of cardiac hypertrophy. Our first finding was that angiotensin-(1–9) can induce mitochondrial fusion through DRP1 phosphorylation. Secondly, angiotensin-(1–9) blocked mitochondrial fission and intracellular calcium dysregulation in a model of norepinephrine-induced cardiomyocyte hypertrophy, preventing the activation of the calcineurin/NFAT signaling pathway. To further investigate angiotensin-(1–9) anti-hypertrophic mechanism, we performed RNA-seq studies, identifying the upregulation of miR-129 under angiotensin-(1–9) treatment. miR-129 decreased the transcript levels of the protein kinase A inhibitor (PKIA), resulting in the activation of the protein kinase A (PKA) signaling pathway. Finally, we showed that PKA activity is necessary for the effects of angiotensin-(1–9) over mitochondrial dynamics, calcium handling and its anti-hypertrophic effects.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - Jan 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Sotomayor-Flores, C., Rivera-Mejías, P., Vásquez-Trincado, C., López-Crisosto, C., Morales, P. E., Pennanen, C., Polakovicova, I., Aliaga-Tobar, V., García, L., Roa, J. C., Rothermel, B. A., Maracaja-Coutinho, V., Ho-Xuan, H., Meister, G., Chiong, M., Ocaranza, M. P., Corvalán, A. H., Parra, V., & Lavandero, S. (Accepted/In press). Angiotensin-(1–9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway. Cell Death and Differentiation. https://doi.org/10.1038/s41418-020-0522-3