Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Department of Pharmacy, Fifth Medical Center, 302 Military Hospital of China, Beijing, 100039, China.
Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
J Ethnopharmacol. 2019 Jun 28;238:111880. doi: 10.1016/j.jep.2019.111880. Epub 2019 Apr 17.
The combined use of Aconiti Lateralis Radix Praeparata (ALRP) and Zingiberis Rhizoma (ZR) are classic compatibilities in China for the treatment of cardiovascular diseases such as increasing myocardial contractility, anti-arrhythmia, reducing myocardial oxygen consumption, and dilating organ blood vessels, etc, thereby exerting anti-heart failure (HF) effects in traditional Chinese herbal medicine. However, comprehensive approaches for understanding the therapeutic effects and mechanisms underlying chronic heart failure (CHF) from the perspective of energy metabolism have not been pursued.
This research was aimed to investigate the effectiveness and potential mechanism of ALRP combined with ZR (1:1) on doxorubicin (DOX)-induced CHF in rats based on an integrated approach that combines network pharmacology analyses and molecular biology.
CHF model was established by the intraperitoneal injection of DOX. ALRP and ZR were intragastrically administrated for three weeks. The detection indices including hemodynamic measurements, myocardial injury marker, and myocardial pathological changes were measured. Network pharmacology analysis was used to illustrate the pathways and network of ALRP and ZR against HF. Mitochondrial energy metabolism pathway associated gene and protein levels of PPARα, PGC-1α and Sirt3 in myocardial tissue were detected by real-time PCR and western blotting, respectively.
The results indicated that ALRP-ZR herbal couple significantly improved the left ventricular function and cardiac enzyme activities in comparison with their single use. Network pharmacology analysis results showed that the pharmacological mechanisms of ALRP-ZR may be related to PPAR energy metabolism pathway. Besides, the outcomes of western-blot and real-time PCR analysis showed that ALRP-ZR significantly upregulates the protein and gene level of PPARα, PGC-1α, and Sirt3.
Network pharmacology analysis would be an effective network analyze workflow which was feasible for evaluating the pharmacological effect of a multi-drug complex system. The Chinese herbal couple ALRP-ZR had a better therapeutic effect than their single-use against DOX-induced CHF, which may be related to enhancing left ventricular function by activating the PPARα/PGC-1α/Sirt3 pathway.
制川乌（ALRP）和姜（ZR）的联合使用是中国治疗心血管疾病的经典配伍，如增加心肌收缩力、抗心律失常、减少心肌耗氧量、扩张器官血管等，从而在中药中发挥抗心力衰竭（HF）作用。然而，从能量代谢的角度综合了解慢性心力衰竭（CHF）的治疗效果和机制的方法尚未被探索。
本研究旨在通过网络药理学分析和分子生物学相结合的综合方法，探讨 ALRP 联合 ZR（1:1）对阿霉素（DOX）诱导的大鼠 CHF 的有效性及潜在机制。
采用腹腔注射 DOX 建立 CHF 模型。给予 ALRP 和 ZR 灌胃治疗 3 周。检测血流动力学指标、心肌损伤标志物和心肌病理变化等指标。采用网络药理学分析方法阐明 ALRP 和 ZR 抗 HF 的通路和网络。实时 PCR 和 Western blot 分别检测心肌组织中线粒体能量代谢相关基因和蛋白水平的过氧化物酶体增殖物激活受体α（PPARα）、过氧化物酶体增殖物激活受体γ 共激活因子 1α（PGC-1α）和沉默调节蛋白 3（Sirt3）。
结果表明，与单药相比，ALRP-ZR 草药联合使用能显著改善左心室功能和心肌酶活性。网络药理学分析结果表明，ALRP-ZR 的药理作用机制可能与 PPAR 能量代谢途径有关。此外，Western blot 和实时 PCR 分析结果表明，ALRP-ZR 能显著上调 PPARα、PGC-1α 和 Sirt3 的蛋白和基因水平。
网络药理学分析是评估多药复杂体系药理作用的有效网络分析方法。ALRP-ZR 中草药复方对 DOX 诱导的 CHF 的治疗效果优于单药，可能与激活 PPARα/PGC-1α/Sirt3 通路增强左心室功能有关。
