Bazi Bushen capsule attenuates cardiac systolic injury via SIRT3/SOD2 pathway in high-fat diet-fed ovariectomized mice
Xiaobin An,
Wentao Xu,
Xinyue Zhao,
Haihui Chen,
Jinan Yang,
Yan Wu,
Dongyang Wang,
Wei Cheng,
Hongrong Li,
Lu Zeng,
Jing Ma,
Qin Wang,
Xuqiao Wang,
Yunlong Hou,
Jing Ai
Affiliations
Xiaobin An
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Wentao Xu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Xinyue Zhao
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Haihui Chen
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Jinan Yang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Yan Wu
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Dongyang Wang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Wei Cheng
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Hongrong Li
New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd., Shijiazhuang, Hebei Province, 050035, China; National Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang, Hebei Province, 050035, China
Lu Zeng
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Jing Ma
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Qin Wang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Xuqiao Wang
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China
Yunlong Hou
New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd., Shijiazhuang, Hebei Province, 050035, China; National Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang, Hebei Province, 050035, China; Corresponding author. New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd., Shijiazhuang, Hebei Province, 050035, China.
Jing Ai
Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), National Key Laboratory of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China; Corresponding author. Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China.
Background: Bazi Bushen capsule (BZBS) is a Chinese herbal compound that is clinically used to treat fatigue and forgetfulness. However, it is still unclear whether and how BZBS affects heart function decline in menopausal women. This study aimed to examine the effect of BZBS on cardiac function in a high-fat diet-fed ovariectomy (HFD-fed OVX) mouse model and elucidate the underlying mechanism of this effect. Methods: The experimental animals were divided into five groups: sham group, HFD-fed OVX group, and BZBS (0.7, 1.4, 2.8 g/kg) intervention groups. Senescence β-galactosidase staining and echocardiography were used to evaluate cardiac function. SwissTargetPrediction, KEGG and GO enrichment analyses were used to screen the underlying mechanism of BZBS. The morphological and functional changes in cardiac mitochondria and the underlying molecular mechanism were assessed by transmission electron microscopy, western blotting and biochemical assays. STRING database was used to analysis protein-protein interaction (PPI) network. Molecular docking studies were employed to predict the interactions of specific BZBS compounds with their protein targets. Results: BZBS treatment ameliorated cardiac senescence and cardiac systole injury in HFD-fed OVX mice. GO and KEGG analyses revealed that the 530 targets of the 14 main components of BZBS were enriched mainly in the oxidative stress-associated pathway, which was confirmed by the finding that BZBS treatment prevented abnormal morphological changes and oxidative stress damage to cardiac mitochondria in HFD-fed OVX mice. Furthermore, the STRING database showed that the targets of BZBS were broadly related to the Sirtuins family. And BZBS upregulated the SIRT3 and elevated the activity of SOD2 in the hearts of HFD-fed OVX mice, which was also verified in vitro. Additionally, we revealed that imperatorin and osthole from the BZBS upregulated the expression of SIRT3 by directly docking with the transcription factors HDAC1, HDAC2, and BRD4, which regulate the expression of SIRT3. Conclusion: This research shows that the antioxidative effect and cardioprotective role of BZBS on HFD-fed OVX mice involves an increase in the activity of the SIRT3/SOD2 pathway, and the imperatorin and osthole of BZBS may play central roles in this process.
