Histology and histopathology · 2025
Data mining based on multiomic data integration to explore the mechanism by which a proprietary Chinese medicine improves cardiac hypertrophy in heart failure.
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Kang Jin-Hua, Li Si-Jing, Li Zi-Ru, Dong Xiao-Ming, Liu Ao, Wu Hong-Yan, Chen Quan-Fu, Long Wen-Jie, Yang Zhong-Qi, He Zhi-Ling
Аннотация
BACKGROUND: Heart failure remains a leading cause of mortality worldwide with limited therapeutic options. Xinyang Tablet (XYT), a clinically used traditional Chinese medicine, demonstrates cardioprotective effects, but its mechanisms against cardiac hypertrophy remain unclear. This study aimed to elucidate the therapeutic mechanisms of XYT in heart failure with a focus on oxidative stress and hypertrophy pathways.
METHODS: Pressure-overload heart failure was induced by transverse aortic constriction (TAC) in mice. Cardiac function was assessed via histology (hematoxylin-eosin [H&E], Masson's trichrome), oxidative stress markers (dihydroethidium [DHE] staining, superoxide dismutase [SOD]/malondialdehyde [MDA]/glutathione peroxidase [GSH-Px] assays), and molecular analyses. In vitro, angiotensin II (AngII)-treated HL-1 cardiomyocytes evaluated hypertrophy and oxidative stress responses. Multiomic approaches, including ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS), network pharmacology, RNA sequencing (RNA-seq), and single-cell RNA sequencing (scRNA-seq), identified XYT's bioactive compounds and hub targets, validated by AKT inhibitor (MK-2206) experiments.
RESULTS: XYT attenuated TAC-induced cardiac hypertrophy and fibrosis, reducing heart volume, cardiomyocyte cross-sectional area, and fibrotic markers (collagen type I alpha 1 [COL1A1]/collagen type III alpha 1 [COL3A1]). XYT suppressed oxidative stress by decreasing reactive oxygen species (ROS)/NADPH oxidase 2 (NOX2)/NOX4 while increasing superoxide dismutase 2 (SOD2)/GSH-Px in vivo and in vitro. Bioinformatics identified 18 hub genes (e.g., histone deacetylase 2 [HDAC2], SOD2) and enriched phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)/oxidative stress pathways. XYT inhibited HDAC2/AKT/glycogen synthase kinase-3β (GSK-3β) phosphorylation, while AKT inhibition with MK-2206 mimicked XYT's protective effects.
CONCLUSION: XYT ameliorates heart failure by targeting HDAC2 to suppress AKT/GSK-3β signaling, mitigating oxidative stress, cardiac hypertrophy, and fibrosis, providing mechanistic evidence for clinical translation.
METHODS: Pressure-overload heart failure was induced by transverse aortic constriction (TAC) in mice. Cardiac function was assessed via histology (hematoxylin-eosin [H&E], Masson's trichrome), oxidative stress markers (dihydroethidium [DHE] staining, superoxide dismutase [SOD]/malondialdehyde [MDA]/glutathione peroxidase [GSH-Px] assays), and molecular analyses. In vitro, angiotensin II (AngII)-treated HL-1 cardiomyocytes evaluated hypertrophy and oxidative stress responses. Multiomic approaches, including ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS), network pharmacology, RNA sequencing (RNA-seq), and single-cell RNA sequencing (scRNA-seq), identified XYT's bioactive compounds and hub targets, validated by AKT inhibitor (MK-2206) experiments.
RESULTS: XYT attenuated TAC-induced cardiac hypertrophy and fibrosis, reducing heart volume, cardiomyocyte cross-sectional area, and fibrotic markers (collagen type I alpha 1 [COL1A1]/collagen type III alpha 1 [COL3A1]). XYT suppressed oxidative stress by decreasing reactive oxygen species (ROS)/NADPH oxidase 2 (NOX2)/NOX4 while increasing superoxide dismutase 2 (SOD2)/GSH-Px in vivo and in vitro. Bioinformatics identified 18 hub genes (e.g., histone deacetylase 2 [HDAC2], SOD2) and enriched phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)/oxidative stress pathways. XYT inhibited HDAC2/AKT/glycogen synthase kinase-3β (GSK-3β) phosphorylation, while AKT inhibition with MK-2206 mimicked XYT's protective effects.
CONCLUSION: XYT ameliorates heart failure by targeting HDAC2 to suppress AKT/GSK-3β signaling, mitigating oxidative stress, cardiac hypertrophy, and fibrosis, providing mechanistic evidence for clinical translation.