芪参颗粒通过调节脂肪酸和葡萄糖代谢对心力衰竭大鼠发挥心脏保护作用。

Qishen granules exerts cardioprotective effects on rats with heart failure via regulating fatty acid and glucose metabolism.

作者信息

Gao Kuo, Zhang Jian, Gao Pengrong, Wang Qiyan, Liu Ying, Liu Junjie, Zhang Yili, Li Yan, Chang Hong, Ren Ping, Liu Jinmin, Wang Yong, Wang Wei

机构信息

1Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, 100078 China.

2School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029 China.

出版信息

Chin Med. 2020 Mar 4;15:21. doi: 10.1186/s13020-020-0299-9. eCollection 2020.

BACKGROUND

granules (QSG) has been applied to treat heart failure (HF) for decades. Our previous transcriptomics study has suggested that granules (QSG) could regulate the pathways of cardiac energy metabolism in HF, but the specific regulatory mechanism has not yet been clarified. This study was to investigate the potential mechanism of QSG in regulating myocardial fatty acid (FA) and glucose metabolism in a rat model of HF.

METHODS

The model of HF was induced by left anterior descending coronary artery ligation. Cardiac structure and function were assessed by cine magnetic resonance imaging (MRI) and echocardiography. Level of glucose metabolism was non-invasively evaluated by F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). Blood lipid levels were determined by enzymatic analysis. The mitochondrial ultrastructure was observed with a transmission electron microscope. The critical proteins related to FA metabolism, glucose metabolism and mitochondrial function were measured by western blotting. The ANOVA followed by a Fisher's LSD test was used for within-group comparisons.

RESULTS

QSG ameliorated cardiac functions and attenuated myocardial remodeling in HF model. The levels of serum TC, TG and LDL-C were significantly reduced by QSG. The proteins mediating FA uptake, transportation into mitochondria and β-oxidation (FAT/CD36, CPT1A, ACADL, ACADM, ACAA2 and SCP2) as well as the upstreaming transcriptional regulators of FA metabolism (PPARα, RXRα, RXRβ and RXRγ) were up-regulated by QSG. As to glucose metabolism, QSG inhibited glycolytic activity by decreasing LDHA, while stimulated glucose oxidation by decreasing PDK4. Furthermore, QSG could facilitate tricarboxylic acid cycle, promote the transportation of ATP from mitochondria to cytoplasm and restore the mitochondrial function by increasing SUCLA2, CKMT2 and PGC-1α and decreasing UCP2 simultaneously.

CONCLUSION

QSG improved myocardial energy metabolism through increasing FA metabolism,inhibiting uncoupling of glycolysis from glucose oxidation.

背景

芪苈强心颗粒（QSG）已应用于心力衰竭（HF）的治疗数十年。我们之前的转录组学研究表明，芪苈强心颗粒（QSG）可调节HF中心脏能量代谢的途径，但其具体调控机制尚未阐明。本研究旨在探讨QSG在HF大鼠模型中调节心肌脂肪酸（FA）和葡萄糖代谢的潜在机制。

方法

通过左冠状动脉前降支结扎诱导HF模型。通过电影磁共振成像（MRI）和超声心动图评估心脏结构和功能。通过F-氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描（PET/CT）无创评估葡萄糖代谢水平。通过酶分析测定血脂水平。用透射电子显微镜观察线粒体超微结构。通过蛋白质印迹法检测与FA代谢、葡萄糖代谢和线粒体功能相关的关键蛋白。组内比较采用方差分析（ANOVA），随后进行Fisher最小显著差异检验（LSD检验）。

结果

QSG改善了HF模型的心脏功能并减轻了心肌重塑。QSG显著降低了血清总胆固醇（TC）、甘油三酯（TG）和低密度脂蛋白胆固醇（LDL-C）水平。介导FA摄取、转运至线粒体和β-氧化的蛋白（脂肪酸转运蛋白/脂肪酸转位酶（FAT/CD36）、肉碱棕榈酰转移酶1A（CPT1A）、酰基辅酶A脱氢酶长链（ACADL）、酰基辅酶A脱氢酶中链（ACADM）、乙酰辅酶A酰基转移酶2（ACAA2）和短链脱氢酶/还原酶家族2（SCP2））以及FA代谢的上游转录调节因子（过氧化物酶体增殖物激活受体α（PPARα）、视黄酸X受体α（RXRα）、视黄酸X受体β（RXRβ）和视黄酸X受体γ（RXRγ））均被QSG上调。关于葡萄糖代谢，QSG通过降低乳酸脱氢酶A（LDHA）抑制糖酵解活性，同时通过降低丙酮酸脱氢酶激酶4（PDK4）刺激葡萄糖氧化。此外，QSG可促进三羧酸循环，通过增加琥珀酸辅酶A连接酶A亚基2（SUCLA2）、肌酸激酶线粒体同工酶2（CKMT2）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）并同时降低解偶联蛋白2（UCP2）来促进ATP从线粒体向细胞质的转运并恢复线粒体功能。