Aims

Abnormal mitochondrial metabolism is an essential factor for excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), which drives the pathological process of pulmonary arterial hypertension (PAH). 3-Bromopyruvate (3-BrPA) is an effective glycolytic inhibitor that improves mitochondrial metabolism, thereby repressing anomalous cell proliferation.

Main methods

An experimental PAH model was established by injection of monocrotaline (MCT) in male Sprague Dawley rats, following which rats were assigned to three groups: control, MCT, and 3-BrPA groups. Three days post injection of MCT, rats were treated with 3-BrPA or vehicle for 4 weeks. At the end of the study, hemodynamic data were measured to confirm PAH condition. Indicators of pulmonary arterial and right ventricular (RV) remodeling as well as the proliferative ability of PASMCs were assayed. Additionally, mitochondrial morphology and function, and antiglycolytic and antiproliferative pathways and genes were analyzed.

Key findings

Treatment with 3-BrPA effectively improved pulmonary vascular remodeling and right ventricular function, inhibited PASMC proliferation, and preserved mitochondrial morphology and function. Besides, 3-BrPA treatment inhibited the PI3K/AKT/mTOR pathway and regulated the expression of antiproliferative genes in PASMCs. However, bloody ascites, bloating, and cirrhosis of organs were observed in some 3-BrPA treated rats.

Significance

3-BrPA acts as an important glycolytic inhibitor to improve energy metabolism and reverse the course of PAH. However, 3-BrPA is associated with side effects in MCT-induced rats, indicating that it should be caution in drug delivery dosage, and further studies are needed to evaluate this toxicological mechanism.

中文翻译：

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3-溴丙酮酸盐可改善线粒体代谢，改善肺动脉高压。

目的

线粒体代谢异常是导致肺动脉平滑肌细胞（PASMC）过度增殖的重要因素，而肺动脉平滑肌细胞过度增殖会驱动肺动脉高压（PAH）的病理过程。3-Bromopyruvate（3-BrPA）是一种有效的糖酵解抑制剂，可改善线粒体代谢，从而抑制异常细胞增殖。

主要方法

通过在雄性Sprague Dawley大鼠中注射Monocrotaline（MCT）建立实验性PAH模型，然后将大鼠分为三组：对照组，MCT和3-BrPA组。注射MCT后三天，将大鼠用3-BrPA或溶媒治疗4周。在研究结束时，测量血流动力学数据以确认PAH状况。测定了肺动脉和右心室（RV）重塑的指标以及PASMC的增殖能力。此外，分析了线粒体的形态和功能，以及抗糖酵解和抗增殖的途径和基因。

主要发现

3-BrPA治疗可有效改善肺血管重构和右心室功能，抑制PASMC增殖，并保留线粒体形态和功能。此外，3-BrPA处理抑制了PASMCs中PI3K / AKT / mTOR通路并调节了抗增殖基因的表达。然而，在一些用3-BrPA处理的大鼠中观察到器官的血性腹水，腹胀和肝硬化。

意义

3-BrPA是重要的糖酵解抑制剂，可改善能量代谢并逆转PAH的进程。然而，3-BrPA与MCT诱导的大鼠的副作用有关，这表明在给药剂量上应谨慎，还需要进一步研究以评估这种毒理学机理。