Angiotensin-(1-9) prevents cardiomyocyte hypertrophy via miR-129-3p/PKIA/PKA signaling pathway
Professor Advisor
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Lavandero González, Sergio
Professor Advisor
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Corvalán Rodríguez, Alejandro Hernán
Professor Advisor
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Meister, Gunter
Author
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Sotomayor Flores, Cristian Alejandro
Admission date
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2021-01-27T22:49:03Z
Available date
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2021-01-27T22:49:03Z
Publication date
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2020
Identifier
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https://repositorio.uchile.cl/handle/2250/178377
General note
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Doctorado en bioquímica
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Abstract
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Angiotensin-(1-9) is a peptide from the non-canonical renin-angiotensin system with anti-hypertrophic effects in cardiomyocytes via an unknown mechanism. Our previous work proved that this peptide induces mitochondrial fusion through Drp1 phosphorylation and prevented norepinephrine-elicited mitochondrial fission. In the present work, we aimed to elucidate the underlying mechanism by which angiotensin-(1-9) could prevent cardiomyocyte hypertrophy together with its effects over mitochondrial dynamics evaluating the possible link between them and the signaling pathways activated during hypertrophy. Here we show, for the first time, that angiotensin-(1-9) prevents intracellular calcium dysregulation and the activation of Calcineurin/NFAT signaling pathway at a transcription and protein level in a model of norepinephrine-induced cardiomyocyte hypertrophy. To further investigate the anti-hypertrophic mechanism of angiotensin-(1-9), 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 the mere activation of PKA by angiotensin-(1-9) accounted for its effects on calcium handling and cardiomyocyte hypertrophy
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Patrocinador
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CONICYT Doctorado 21140671; International Ph.D. program at Universität Regensburg (iPUR) scholarship (Alemania); FONDAP 15130011; FONDECYT 1161156; FONDECYT 1200490