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Angiotensin-(1-9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via miR-129-3p/PKIA pathway.
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2020-03-09 , DOI: 10.1038/s41418-020-0522-3
Cristian Sotomayor-Flores 1, 2 , Pablo Rivera-Mejías 1 , César Vásquez-Trincado 1 , Camila López-Crisosto 1 , Pablo E Morales 1 , Christian Pennanen 1 , Iva Polakovicova 3 , Víctor Aliaga-Tobar 1 , Lorena García 1 , Juan Carlos Roa 4 , Beverly A Rothermel 5 , Vinicius Maracaja-Coutinho 1 , Hung Ho-Xuan 2 , Gunter Meister 2 , Mario Chiong 1 , María Paz Ocaranza 3, 6 , Alejandro H Corvalán 3, 7 , Valentina Parra 1, 8, 9 , Sergio Lavandero 1, 5, 7
Affiliation  

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.



中文翻译:

血管紧张素-(1-9) 通过 miR-129-3p/PKIA 途径控制线粒体动力学来防止心肌细胞肥大。

血管紧张素-(1–9) 是一种来自非经典肾素-血管紧张素系统的肽,通过未知机制在心肌细胞中具有抗肥厚作用。在本研究中,我们的目的是阐明这一点,最初基于我们小组和同事之前的工作,他们证明了线粒体形态紊乱和钙处理之间的关系,与心脏肥大的情况相关。我们的第一个发现是血管紧张素-(1-9) 可以通过 DRP1 磷酸化诱导线粒体融合。其次,在去甲肾上腺素诱导的心肌细胞肥大模型中,血管紧张素-(1-9)可阻断线粒体裂变和细胞内钙失调,从而阻止钙调神经磷酸酶/NFAT信号通路的激活。为了进一步研究血管紧张素-(1-9) 的抗肥厚机制,我们进行了 RNA-seq 研究,确定了血管紧张素-(1-9) 治疗下 miR-129 的上调。miR-129 降低蛋白激酶 A 抑制剂 (PKIA) 的转录水平,从而激活蛋白激酶 A (PKA) 信号通路。最后,我们证明 PKA 活性对于血管紧张素-(1-9) 对线粒体动力学、钙处理及其抗肥大作用的影响是必要的。

更新日期:2020-04-24
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