TY - JOUR
T1 - Angiotensin-(1–9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway
AU - Sotomayor-Flores, Cristian
AU - Rivera-Mejías, Pablo
AU - Vásquez-Trincado, César
AU - López-Crisosto, Camila
AU - Morales, Pablo E.
AU - Pennanen, Christian
AU - Polakovicova, Iva
AU - Aliaga-Tobar, Víctor
AU - García, Lorena
AU - Roa, Juan Carlos
AU - Rothermel, Beverly A.
AU - Maracaja-Coutinho, Vinicius
AU - Ho-Xuan, Hung
AU - Meister, Gunter
AU - Chiong, Mario
AU - Ocaranza, María Paz
AU - Corvalán, Alejandro H.
AU - Parra, Valentina
AU - Lavandero, Sergio
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41418-020-0522-3
DO - 10.1038/s41418-020-0522-3
M3 - Article
C2 - 32152556
AN - SCOPUS:85081677836
VL - 27
SP - 2586
EP - 2604
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 9
ER -