angoroside-c and Disease-Models--Animal

Heart failure (HF), the main cause of death in patients with many cardiovascular diseases, has been reported to be closely related to the complicated pathogenesis of autophagy, apoptosis, and inflammation. Notably, Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese medicine (TCM) used to treat cardiovascular disease; however, the main active components and their relevant mechanisms remain to be discovered. Based on our previous ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) results, we identified angoriside C (AC) and 3,5-dicaffeoylquinic acid (3,5-DiCQA) as the main active components of SMYAD. In vivo results showed that AC and 3,5-DiCQA effectively improved cardiac function, reduced the fibrotic area, and alleviated isoproterenol (ISO)-induced myocarditis in rats. Moreover, AC and 3,5-DiCQA inhibited ISO-induced autophagic cell death by inhibiting the PDE5A/AKT/mTOR/ULK1 pathway and inhibited ISO-induced apoptosis by inhibiting the TLR4/NOX4/BAX pathway. In addition, the autophagy inhibitor 3-MA was shown to reduce ISO-induced apoptosis, indicating that ISO-induced autophagic cell death leads to excess apoptosis. Taken together, the main active components AC and 3,5-DiCQA of SMYAD inhibit the excessive autophagic cell death and apoptosis induced by ISO by inhibiting the PDE5A-AKT and TLR4-NOX4 pathways, thereby reducing myocardial inflammation and improving heart function to alleviate and treat a rat ISO-induced heart failure model and cell heart failure models. More importantly, the main active components of SMYAD will provide new insights into a promising strategy that will promote the discovery of more main active components of SMYAD for therapeutic purposes in the future.

Topics: Animals; Apoptosis; Autophagy; Cell Line; Cell Survival; Chlorogenic Acid; Coumaric Acids; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Drugs, Chinese Herbal; Heart Failure; Isoproterenol; Male; Myoblasts; Myocardium; NADPH Oxidase 4; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Toll-Like Receptor 4; Trisaccharides

Our previous study reveals that total rough extract of Radix Scrophulariae has a beneficial effect on ventricular remodeling.. After carrying out a series of preliminary experiments, we speculated that angoroside C may be the effective agent.. After oral administration, the effect of angoroside C on ventricular remodeling was evaluated by using a pressure-overloaded rat model, some related indexes were detected in vivo.. A model of pressure overloaded ventricular remodeling was produced by abdominal aortic constriction (AAC) in rats. The sham-operated rats underwent an identical surgical procedure except for AAC. AAC rats were randomly divided into five groups: model control group, three angoroside C treated groups (7.5, 15 and 30 mg·kg(-1)) and captopril treated group (40 mg·kg(-1)). The rats were orally administered with the corresponding drugs or drinking water for 4 weeks. The levels of blood pressure (BP), left ventricular weight index (LVWI) and heart weight index (HWI) were detected. Myocardium tissue was stained with hematoxylin and eosin or picric acid/sirius red for cardiomyocyte cross-section area or collagen content measurements respectively. The concentrations of angiotensin Ⅱ (Ang Ⅱ), hydroxyproline (Hyp), matrix metalloproteinase 2 (MMP-2), MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in myocardium or serum were determined. Real-time RT-PCR was performed to detect the mRNA expressions of endothelin 1 (ET-1), transforming growth factor β1 (TGF-β1).. Angoroside C significantly reduced the BP, LVWI and HWI, decreased the content of Ang Ⅱ, Hyp, diminished cross sectional area of cardiomyocytes and ameliorated collagen deposition. Additionally, it markedly reduced collagen I and III expressions and regulated matrix metalloproteinase-2, 9 and inhibitors of metalloproteinase expressions. Angoroside C also down regulated the gene expressions of ET-1 and TGF-β1mRNA in myocardium.. Angoroside C has beneficial effects against ventricular remodeling. The mechanism is likely to be related to decreasing the level of Ang Ⅱ, attenuating the mRNA expressions of ET-1 and TGF-β1.

Topics: Angiotensin II; Animals; Aorta; Blood Pressure; Captopril; Collagen; Constriction, Pathologic; Coumaric Acids; Disease Models, Animal; Endothelin-1; Heart; Heart Rate; Hydroxyproline; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Scrophularia; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1; Trisaccharides; Ventricular Remodeling