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

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...

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Published in:Cell death and differentiation 2020-09, Vol.27 (9), p.2586-2604
Main Authors: Sotomayor-Flores, Cristian, Rivera-Mejías, Pablo, Vásquez-Trincado, César, López-Crisosto, Camila, Morales, Pablo E, Pennanen, Christian, Polakovicova, Iva, Aliaga-Tobar, Víctor, García, Lorena, Roa, Juan Carlos, Rothermel, Beverly A, Maracaja-Coutinho, Vinicius, Ho-Xuan, Hung, Meister, Gunter, Chiong, Mario, Ocaranza, María Paz, Corvalán, Alejandro H, Parra, Valentina, Lavandero, Sergio
Format: Article
Language:English
Subjects:
Angiotensin
Angiotensin I - pharmacology
Animals
Animals, Newborn
Calcineurin
Calcium (intracellular)
Calcium (mitochondrial)
Calcium - metabolism
Calcium signalling
Cardiomyocytes
Cyclic AMP-Dependent Protein Kinases - metabolism
Cytosol - metabolism
Dynamins - metabolism
Enzyme inhibitors
Hypertrophy
Intracellular Signaling Peptides and Proteins - metabolism
Kinases
MicroRNAs - genetics
MicroRNAs - metabolism
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondrial Dynamics - drug effects
Models, Biological
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Myocytes, Cardiac - ultrastructure
NF-AT protein
NFATC Transcription Factors - metabolism
Norepinephrine
Norepinephrine - pharmacology
Peptide Fragments - pharmacology
Phosphorylation
Phosphorylation - drug effects
Protein kinase A
Protein kinase A inhibitors
Rats, Sprague-Dawley
Renin
Ribonucleic acid
RNA
Signal transduction
Signal Transduction - drug effects
Transcription
Up-Regulation - drug effects
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Summary: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.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-020-0522-3