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Pulmonary arterial hypertension induces the release of circulating extracellular vesicles with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats

Abstract

Pulmonary arterial hypertension (PAH) is characterized by increased resistance of the pulmonary vasculature and afterload imposed on the right ventricle (RV). Two major contributors to the worsening of this disease are oxidative stress and mitochondrial impairment. This study aimed to explore the effects of monocrotaline (MCT)-induced PAH on redox and mitochondrial homeostasis in the RV and brain and how circulating extracellular vesicle (EV) signaling is related to these phenomena. Wistar rats were divided into control and MCT groups (60 mg/kg, intraperitoneal), and EVs were isolated from blood on the day of euthanasia (21 days after MCT injections). There was an oxidative imbalance in the RV, brain, and EVs of MCT rats. PAH impaired mitochondrial function in the RV, as seen by a decrease in the activities of mitochondrial complex II and citrate synthase and manganese superoxide dismutase (MnSOD) protein expression, but this function was preserved in the brain. The key regulators of mitochondrial biogenesis, namely, proliferator-activated receptor gamma coactivator 1-alpha and sirtuin 1, were poorly expressed in the EVs of MCT rats, and this result was positively correlated with MnSOD expression in the RV and negatively correlated with MnSOD expression in the brain. Based on these findings, we can conclude that the RV is severely impacted by the development of PAH, but this pathological injury may signal the release of circulating EVs that communicate with different organs, such as the brain, helping to prevent further damage through the upregulation of proteins involved in redox and mitochondrial function.

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Acknowledgements

This work was supported by research grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). We thank Tânia Regina Fernandes Piedras for all technical assistance during the development of this research.

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Corssac, G.B., Bonetto, J.P., Campos-Carraro, C. et al. Pulmonary arterial hypertension induces the release of circulating extracellular vesicles with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats. Hypertens Res (2021). https://doi.org/10.1038/s41440-021-00660-y

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Keywords

  • Extracellular vesicles
  • Mitochondrial function
  • Monocrotaline
  • Oxidative stress
  • Pulmonary hypertension

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