Postgraduate Program in Biological Sciences: Physiology, Department of Physiology, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.
Postgraduate Program in Biological Sciences: Pharmacology and Therapeutic, Department of Pharmacology, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.
Hypertens Res. 2021 Aug;44(8):918-931. doi: 10.1038/s41440-021-00660-y. Epub 2021 Apr 19.
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.
肺动脉高压（PAH）的特征是肺血管阻力增加和右心室（RV）后负荷增加。导致这种疾病恶化的两个主要因素是氧化应激和线粒体损伤。本研究旨在探讨野百合碱（MCT）诱导的 PAH 对 RV 和大脑中氧化还原和线粒体稳态的影响，以及循环细胞外囊泡（EV）信号与这些现象的关系。Wistar 大鼠分为对照组和 MCT 组（60mg/kg，腹腔内），并在安乐死当天（MCT 注射后 21 天）从血液中分离 EV。MCT 大鼠的 RV、大脑和 EV 存在氧化失衡。PAH 降低了 RV 中线粒体复合物 II 和柠檬酸合酶以及锰超氧化物歧化酶（MnSOD）蛋白表达的活性，从而损害了线粒体功能，但在大脑中保留了这种功能。线粒体生物发生的关键调节因子，即过氧化物酶体增殖物激活受体γ共激活因子 1-α和 Sirtuin 1，在 MCT 大鼠的 EV 中表达不佳，这一结果与 RV 中的 MnSOD 表达呈正相关，与大脑中的 MnSOD 表达呈负相关。基于这些发现，我们可以得出结论，RV 受到 PAH 发展的严重影响，但这种病理损伤可能会通过上调与氧化还原和线粒体功能相关的蛋白，释放与不同器官（如大脑）进行交流的循环 EV，从而有助于防止进一步的损伤。
