Department of Respirology (B2), Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan.
Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba 260‑8670, Japan.
Mol Med Rep. 2021 Apr;23(4). doi: 10.3892/mmr.2021.11866. Epub 2021 Jan 26.
It is generally considered that there is an increase in glycolysis in the hypertrophied right ventricle (RV) during pulmonary hypertension (PH), which leads to a decrease in glucose oxidation through the tricarboxylic acid (TCA) cycle. Although recent studies have demonstrated that fatty acid (FA) and glucose accumulated in the RV of patients with PH, the details of this remain to be elucidated. The purpose of the current study was to assess the metabolic remodeling in the RV of rats with PH using a metabolic analysis. Male rats were treated with the vascular endothelial growth factor receptor blocker SU5416 followed by 3 weeks of hypoxic conditions and 5 weeks of normoxic conditions (Su/Hx rats). Hemodynamic measurements were conducted, and the RV was harvested for the measurement of metabolites. A metabolomics analysis revealed a decreasing trend in the levels of alanine, argininosuccinic acid and downstream TCA cycle intermediates, including fumaric and malic acid and an increasing trend in branched‑chain amino acids (BCAAs) in Su/Hx rats compared with the controls; however, no trends in glycolysis were indicated. The FA metabolomics analysis also revealed a decreasing trend in the levels of long‑chain acylcarnitines, which transport FA from the cytosol to the mitochondria and are essential for beta‑oxidation. The current study demonstrated that the TCA cycle was less activated because of a decreasing trend in the expression of fumaric acid and malic acid, which might be attributable to the expression of adenylosuccinic acid and argininosuccinic acid. These results suggest that dysregulated BCAA metabolism and a decrease in FA oxidation might contribute to the reduction of the TCA cycle reactions.
一般认为，在肺动脉高压（PH）期间，肥厚的右心室（RV）中的糖酵解增加，这导致通过三羧酸（TCA）循环的葡萄糖氧化减少。尽管最近的研究表明 PH 患者的 RV 中积累了脂肪酸（FA）和葡萄糖，但这方面的细节仍有待阐明。本研究的目的是使用代谢分析评估 PH 大鼠 RV 的代谢重塑。雄性大鼠用血管内皮生长因子受体阻滞剂 SU5416 处理，然后进行 3 周缺氧和 5 周常氧条件（Su/Hx 大鼠）。进行血流动力学测量，并收获 RV 以测量代谢物。代谢组学分析显示，与对照组相比，Su/Hx 大鼠中的丙氨酸、精氨琥珀酸和下游 TCA 循环中间产物（包括富马酸和苹果酸）的水平呈下降趋势，支链氨基酸（BCAA）呈上升趋势；然而，糖酵解没有表现出趋势。FA 代谢组学分析还显示长链酰基辅酶 A 的水平呈下降趋势，长链酰基辅酶 A 将 FA 从细胞质转运到线粒体，是β-氧化所必需的。本研究表明，由于富马酸和苹果酸表达减少，TCA 循环的激活程度降低，这可能归因于腺嘌呤核苷酸和精氨琥珀酸的表达。这些结果表明，BCAA 代谢失调和 FA 氧化减少可能导致 TCA 循环反应减少。
