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Astragaloside IV Attenuates the Myocardial Injury Caused by Adriamycin by Inhibiting Autophagy.

ABSTRACT: Astragaloside IV (ASIV) is the main active component of Astragalus, and can ameliorate cardiomyocyte hypertrophy, apoptosis and fibrosis. In this experiment, we studied how ASIV reduces the cardiotoxicity caused by adriamycin and protects the heart. To this end, rats were randomly divided into the control, ADR, ADR + ASIV and ASIV groups (n = 6). Echocardiography was used to observe cardiac function, HE staining was used to observe myocardial injury, TUNEL staining was used to observe myocardial cell apoptosis, and immunofluorescence and Western blotting was used to observe relevant proteins expression. Experiments have shown that adriamycin can damage heart function in rats, and increase the cell apoptosis index, autophagy level and oxidative stress level. Further results showed that ADR can inhibit the PI3K/Akt pathway. ASIV treatment can significantly improve the cardiac function of rats treated with ADR and regulate autophagy, oxidative stress and apoptosis. Our findings indicate that ASIV may reduce the heart damage caused by adriamycin by activating the PI3K/Akt pathway.

SUBMITTER: Luo LF

PROVIDER: S-EPMC8184095 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Astragaloside IV Attenuates the Myocardial Injury Caused by Adriamycin by Inhibiting Autophagy.

Luo Li-Fei LF Qin Lu-Yun LY Wang Jian-Xin JX Guan Peng P Wang Na N Ji En-Sheng ES

Frontiers in pharmacology 20210524

Astragaloside IV (ASIV) is the main active component of <i>Astragalus</i>, and can ameliorate cardiomyocyte hypertrophy, apoptosis and fibrosis. In this experiment, we studied how ASIV reduces the cardiotoxicity caused by adriamycin and protects the heart. To this end, rats were randomly divided into the control, ADR, ADR + ASIV and ASIV groups (<i>n</i> = 6). Echocardiography was used to observe cardiac function, HE staining was used to observe myocardial injury, TUNEL staining was used to obse ...[more]

PMID: 34108879

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Project description:BackgroundAstragaloside IV (As-IV) and Tanshinone IIA (Ta-IIA) are the main ingredients of traditional Chinese medicinal Astragalus membranaceus (Fisch.) Bunge and Salvia miltiorrhiza Bunge, respectively, both of which have been employed in the treatment of cardiovascular diseases. Nevertheless, the efficacy of the combination (Co) of Ta-IIA and As-IV for cardiovascular diseases remain unclear and warrant further investigation. This study aimed to investigate the efficacy and the underlying molecular mechanism of Co in treating myocardial ischemia-reperfusion injury (MIRI).MethodsIn order to assess the efficacy of Co, an in vivo MIRI mouse model was created by temporarily blocking the coronary arteries for 30 min and then releasing the blockage. Parameters such as blood myocardial enzymes, infarct size, and ventricular function were measured. Additionally, in vitro experiments were conducted using HL1 cells in both hypoxia-reoxygenation model and oxidative stress models. The apoptosis rate, expression levels of apoptosis-related proteins, oxidative stress indexes, and release of inflammatory factors were detected. Furthermore, molecular docking was applied to examine the binding properties of Ta-IIA and As-IV to STING, and western blotting was performed to analyze protein expression of the STING pathway. Additionally, the protective effect of Ta-IIA, As-IV and Co via inhibiting STING was further confirmed in models of knockdown STING by siRNA and adding STING agonist.ResultsBoth in vitro and in vivo data demonstrated that, compared to Ta-IIA or As-IV alone, the Co exhibited superior efficacy in reducing the area of myocardial infarction, lowering myocardial enzyme levels, and promoting the recovery of myocardial contractility. Furthermore, the Co showed more potent anti-apoptosis, antioxidant, and anti-inflammation effects. Additionally, the Co enhanced the inhibitory effects of Ta-IIA and As-IV on STING phosphorylation and the activation of STING signaling pathway. However, the administration of a STING agonist attenuated the protective effects of the Co, Ta-IIA, and As-IV by compromising their anti-apoptotic, antioxidant, and anti-inflammatory effects in MIRI.ConclusionCompared to the individual administration of Ta-IIA or As-IV, the combined treatment demonstrated more potent ability in inhibiting apoptosis, oxidative stress, inflammation, and the STING signaling pathway in the context of MIRI, indicating a more powerful protective effect against MIRI.

Project description:Astragalus membranaceus is a traditional Chinese medicine and has been widely used in treating cardiovascular diseases (CVDs), such as asthma, edema, and chest tightness. Astragaloside IV (AS-IV), one of the major active components extracted from Astragalus membranaceus, has a series of pharmacological effects, including inhibiting inflammation, regulating energy metabolism, reducing oxidative stress and apoptosis. However, the effect of AS-IV on myocardial infarction (MI) and the underlying molecular mechanism remains unclear. The purpose of our study is to investigate the effects of AS-IV on MI-induced myocardial fibrosis and cardiac remodeling and to elucidate its underlying mechanisms. MI was induced by ligation of the left anterior descending (LAD) coronary artery. Echocardiography was used to evaluate cardiac function in mice. Pathological changes in cardiac tissues were analyzed with hematoxylin and eosin (H&E) staining, Masson staining, and wheat germ agglutinin (WGA) staining. Immunohistochemistry was used to detect the expression of fibrosis and inflammation-related proteins. Immunofluorescence and flow cytometry were used to detect ROS level. The expressions of α-SMA, Collagen I, NLRP3, cleaved cas-1, cleaved IL-18, cleaved IL-β, GSDMD-N, and cleaved caspase-1 were examined using western blot. The results of cardiac ultrasound showed that AS-IV could improve poor ventricular remodeling, myocardial pathological staining showed that AS-IV could significantly reduce the myocardial fibrosis and myocardial hypertrophy, ROS levels were also significantly reduced, and the protein expression of NLRP3/Caspase-1/GSDMD signaling pathway was remarkably decreased in the AS-IV group. Furthermore, immunohistochemical staining results showed that the expression of myocardial macrophages and neutrophils in AS-IV group decreased significantly, to further investigate whether the reduction of myocardial pyroptosis by AS-IV is related to the regulation of macrophages, in vitro, AS-IV was selected to stimulate bone marrow-derived macrophages (BMDMs). Our findings indicated that AS-IV protective effect of the heart might be related to the reduction of macrophage pyroptosis. These results demonstrate that AS-IV alleviated MI-induced myocardial fibrosis and cardiac remodeling by suppressing ROS/Caspase-1/GSDMD signaling pathway, AS-IV should be further studied in the future.

Project description:BackgroundIn recent years, diabetic kidney disease (DKD) has emerged as a prominent factor contributing to end-stage renal disease. Tubulointerstitial inflammation and lipid accumulation have been identified as key factors in the development of DKD. Earlier research indicated that Astragaloside IV (AS-IV) reduces inflammation and oxidative stress, controls lipid accumulation, and provides protection to the kidneys. Nevertheless, the mechanisms responsible for its protective effects against DKD have not yet been completely elucidated.PurposeThe primary objective of this research was to examine the protective properties of AS-IV against DKD and investigate the underlying mechanism, which involves CD36, reactive oxygen species (ROS), NLR family pyrin domain containing 3 (NLRP3), and interleukin-1β (IL-1β).MethodsThe DKD rat model was created by administering streptozotocin along with a high-fat diet. Subsequently, the DKD rats and palmitic acid (PA)-induced HK-2 cells were treated with AS-IV. Atorvastatin was used as the positive control. To assess the therapeutic effects of AS-IV on DKD, various tests including blood sugar levels, the lipid profile, renal function, and histopathological examinations were conducted. The levels of CD36, ROS, NLRP3, Caspase-1, and IL-1β were detected using western blot analysis, PCR, and flow cytometry. Furthermore, adenovirus-mediated CD36 overexpression was applied to explore the underlying mechanisms through in vitro experiments.ResultsIn vivo experiments demonstrated that AS-IV significantly reduced hyperglycemia, dyslipidemia, urinary albumin excretion, and serum creatinine levels in DKD rats. Additionally, it improved renal structural abnormalities and suppressed the expression of CD36, NLRP3, IL-1β, TNF-α, and MCP-1. In vitro experiments showed that AS-IV decreased CD36 expression, lipid accumulation, and lipid ROS production while inhibiting NLRP3 activation and IL-1β secretion in PA-induced HK-2 cells.ConclusionAS-IV alleviated renal tubule interstitial inflammation and tubule epithelial cell apoptosis in DKD rats by inhibiting CD36-mediated lipid accumulation and NLRP3 inflammasome activation.

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Astragaloside IV Attenuates the Myocardial Injury Caused by Adriamycin by Inhibiting Autophagy.

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Astragaloside IV Attenuates the Myocardial Injury Caused by Adriamycin by Inhibiting Autophagy.

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