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

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.

SUBMITTER: Sotomayor-Flores C

PROVIDER: S-EPMC7429871 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Sotomayor-Flores Cristian C Rivera-Mejías Pablo P Vásquez-Trincado César C López-Crisosto Camila C Morales Pablo E PE Pennanen Christian C Polakovicova Iva I Aliaga-Tobar Víctor V García Lorena L Roa Juan Carlos JC Rothermel Beverly A BA Maracaja-Coutinho Vinicius V Ho-Xuan Hung H Meister Gunter G Chiong Mario M Ocaranza María Paz MP Corvalán Alejandro H AH Parra Valentina V Lavandero Sergio S

Cell death and differentiation 20200309 9

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 ...[more]

PMID: 32152556

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Project description:BackgroundCardiac hypertrophy is a common pathological process in many cardiac diseases, and persistent cardiac hypertrophy is the main cause of heart failure and sudden cardiogenic death. Thus, it is essential to elucidate the mechanism of cardiac hypertrophy to ensure better prevention and treatment.MethodsThe Human cardiac myocytes (HCMs) were incubated with 100 nmol/L Ang II (Sigma) for 48 hours to induce the in vitro cardiomyocyte hypertrophy model. The [(3H])-leucine incorporation assay was used to evaluate cardiomyocytes hypertrophy. The activities of oxidative stress related enzymes superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and nitric oxide (NO) were detected using corresponding detection kits following standard protocol. Targeting relationship was verified through Bioinformatics analysis and luciferase reporter gene assay. The morphological change of cardiomyocyte was observed through immunofluorescence staining. Expressions of message ribonucleic acid (mRNA) and proteins were detected by quantitative real-time polymerase chain reaction and western blot, respectively.ResultsIn our study, the suppressed expression of micro ribonucleic acid (miRNA)-129-5p and the elevated expression of kelch-like ECH-associated protein 1 (keap-1) were found in the angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model. MiR-129-5p effectively mimics suppressed Ang II-induced hypertrophic responses and oxidative stress. The results also showed that keap-1 was a target of miR-129-5p, and that the miR-129-5p inhibitor promoted cardiomyocyte hypertrophy and oxidative stress by elevating keap-1. Additionally, small interfering RNA (siRNA)-keap-1 activated the nuclear factor erythroid2-related factor 2 (Nrf2) pathway, while the miR-129-5p inhibitor inactivated the Nrf2 pathway by further elevating keap-1. The addition of the Nrf2 pathway activator NK-252 largely weakened the promoting effects of the miR-129-5p inhibitor on the progression of cardiomyocyte hypertrophy by suppressing oxidative stress.ConclusionsIn general, the results indicate that the overexpression of miRNA-129-5p protects against cardiomyocyte hypertrophy by targeting keap-1 via the Nrf2 pathway.

Dataset Information

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

Publications

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

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