Background and objectives Fuzi, the processed product of daughter roots of Aconitum carmichaelii Debx., is a well-known Chinese medicine for the treatment of heart failure (HF) and related cardiac diseases. This study aimed to investigate the molecular mechanism of the cardioprotective effects of Fuzi water decoction (FWD) and Fuzi water-soluble alkaloids (FWA) on the model of HF.
Methods The HF model of rats was prepared through intravenous injection of propafenone hydrochloride. The normal group, model group, FWD-treated groups (1.25 g/kg, 2.5 g/kg, 5 g/kg) and positive group (Shenfu Injection, 3.3 mL/kg) were set up. Heart rate, LV+dp/dtmax, and LV-dp/dtmax were recorded at 5 m, 10 m, 20 m, 30 m, and 60 m after drug administration, respectively. The contents of atrial natriuretic peptide, brain natriuretic peptide (BNP), angiotensin II, and aldosterone in serum were determined 20 m post-administration. An in vitro cardiomyocyte hypertrophy model with HDAC2 overexpression was constructed and verified by lentivirus transfection. The experiment included a blank group, FWD-treated groups (3 mg/mL, 1.5 mg/mL), and FWA-treated groups (4 mg/mL, 2 mg/mL). For transcriptome analysis, the model group, blank group, and FWD-treated group (2.5 g/kg) at 20 m and 60 m in vivo, and different dose groups in vitro, were selected to analyze the therapeutic mechanisms of FWD and FWA.
Results All FWD treatment groups showed an increased heart rate, among which the groups with 2.5 g/kg and 5 g/kg FWD showed better effects, significantly increasing LV+dp/dtmax and LV-dp/dtmax after 20 m of administration and significantly reducing BNP and aldosterone serum levels. In the constructed cardiomyocyte hypertrophy model, HDAC2 expression, atrial natriuretic peptide and BNP protein levels, and cell surface area increased. Transcriptome data from both in vivo and in vitro showed that FWD and FWA could exert cardioprotective effects through pathways such as the PI3K-Akt signaling pathway, NF-κB signaling pathway, and ATP-binding cassette (ABC) transporters, involving key genes such as ITGB1, TLR2, and CDKN1A. Fuzi inhibited the hypertrophic gene HDAC2. Additionally, based on weighted gene co-expression network analysis, ABC transporters may be an important molecular pathway for FWA in treating HF.
Conclusions Both FWD and FWA can ameliorate HF by regulating apoptosis, proliferation, and anti-fibrosis, with ABC transporters potentially being the main pathway for the action of FWA.
Acknowledgments
We thank the State Key Laboratory of Southwest Chinese Medi-cine Resources, Chengdu University of Traditional Chinese Medi-cine, for providing the decoction of FWD and FWA.
Funding
This work was supported by National Natural Science Foundation of China (81891010, 81891012), National Interdisciplinary Innovation Team of Traditional Chinese Medicine (ZYYCXTD-D-202209), Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (2060302), School fund in Chengdu University of TCM (QJRC2022029), Science and technology research project of Sichuan Administration of Traditional Chinese Medicine (Study on the influence of traditional Chinese medicine for nourishing Yin and Quelling wind on clinical evaluation indexes and airway neurogenic inflammation in patients with chronic mild to moderate asthma, 2021MS169) and Chengdu major science and technology application demonstration project (Research and development and application demonstration of immersive Chinese intangible cultural heritage health care experience system, 2022-YF09-00058-SN).
Conflict of interest
The authors have no conflict of interests related to this publication.
Author contributions
Study concept and design (JHG, CP), acquisition of data (JZ, JHG), analysis and interpretation of data (JHG, FXH, JZ), drafting of the manuscript (JZ, DZ), administrative, technical, or material support (CP), and study supervision (XFX). All authors have made a significant contribution to this study and have approved the final manuscript.
Ethical statement
This study was carried out in accordance with the recommenda-tions in the Guidelines for Animal Experimentation of Chengdu University of TCM. The protocol was approved by the Commit-tee on the Ethics of Animal Experiments of Chengdu University of Traditional Chinese Medicine (Protocol Number: 2023020). All surgery was performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering.
Data sharing statement
The dataset used in support of the findings of this study is available from the corresponding author at gaojihai@cdutcm.edu.cn upon request.
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