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.
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Acknowledgements
The authors thank Fidel Albornoz, Gindra Latorre and Sebastian Leiva for their excellent technical assistance.
Funding
This work was supported by grants from the Agencia Nacional de Investigacion y Desarrollo (ANID), Chile: (FONDECYT 1120212 to SL, 1190743 to VP, 3130749 to CP, 11181330 to IP, 1140329 to MC, 11161020 to VM-C and; FONDAP 15130011 to SL, AHC, MC, VP, VM-C, LG, MPO; Anillo ACT192144 to MPO; PAI Insertion Program 79150007 to VP and 79170021 to VM-C; Becas Chile Postdoctoral Fellowship 74120010 to VP), NIH (HD087351 and HD101006 to BAR); American Heart Association (Postdoctoral Fellowship 13POST16520009 to VP and AHA grant 19TPA34920001 to BAR) and ICGEB (CRP-ICGEB Research Grant CRP/CHL18-04 to VP). We are also thankful for the PhD or MSc fellowships from CONICYT Chile to CS-F, PR-M, CV-T, CL-C and PEM.
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Sotomayor-Flores, C., Rivera-Mejías, P., Vásquez-Trincado, C. et al. Angiotensin-(1–9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway. Cell Death Differ 27, 2586–2604 (2020). https://doi.org/10.1038/s41418-020-0522-3
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DOI: https://doi.org/10.1038/s41418-020-0522-3
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