Qin Xiaohan, Lei Chuxiang, Yan Li, Sun Haidan, Liu Xiaoyan, Guo Zhengguang, Sun Wei, Guo Xiaoxiao, Fang Quan
Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Front Mol Biosci. 2022 Jul 5;9:834179. doi: 10.3389/fmolb.2022.834179. eCollection 2022.
Right ventricular failure (RVF) is the independent and strongest predictor of mortality in pulmonary arterial hypertension (PAH), but, at present, there are no preventive and therapeutic strategies directly targeting the failing right ventricle (RV). The underlying mechanism of RV hypertrophy (RVH) and dysfunction needs to be explored in depth. In this study, we used myocardial proteomics combined with metabolomics to elucidate potential pathophysiological changes of RV remodeling in a monocrotaline (MCT)-induced PAH rat model. The proteins and metabolites extracted from the RV myocardium were identified using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). The bioinformatic analysis indicated that elevated intracellular Ca concentrations and inflammation may contribute to myocardial proliferation and contraction, which may be beneficial for maintaining the compensated state of the RV. In the RVF stage, ferroptosis, mitochondrial metabolic shift, and insulin resistance are significantly involved. Dysregulated iron homeostasis, glutathione metabolism, and lipid peroxidation related to ferroptosis may contribute to RV decompensation. In conclusion, we depicted a proteomic and metabolomic profile of the RV myocardium during the progression of MCT-induced PAH, and also provided the insights for potential therapeutic targets facilitating the retardation or reversal of RV dysfunction in PAH.
右心室衰竭（RVF）是肺动脉高压（PAH）患者死亡率的独立且最强预测因素，但目前尚无直接针对衰竭右心室（RV）的预防和治疗策略。RV肥厚（RVH）和功能障碍的潜在机制有待深入探究。在本研究中，我们运用心肌蛋白质组学结合代谢组学，以阐明在野百合碱（MCT）诱导的PAH大鼠模型中RV重塑的潜在病理生理变化。使用无标记液相色谱 - 串联质谱（LC-MS/MS）鉴定从RV心肌中提取的蛋白质和代谢物。生物信息学分析表明，细胞内Ca浓度升高和炎症可能有助于心肌增殖和收缩，这可能有利于维持RV的代偿状态。在RVF阶段，铁死亡、线粒体代谢转变和胰岛素抵抗显著相关。与铁死亡相关的铁稳态失调、谷胱甘肽代谢和脂质过氧化可能导致RV失代偿。总之，我们描绘了MCT诱导的PAH进展过程中RV心肌的蛋白质组学和代谢组学图谱，并为促进PAH中RV功能障碍延缓或逆转的潜在治疗靶点提供了见解。
