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Abstract Aims Astragaloside IV (As-IV) is the major active ingredient of Astragalus membranaceus and has diverse pharmacological activities, including anti-inflammatory and antioxidant effects. However, the beneficial effect of As-IV on protecting vascular endothelial dysfunction is not completely understood. The aim of this study was to investigate the protective effect and mechanism of As-IV on vascular endothelial dysfunction. Materials and methods A diabetes model was established by intraperitoneal injection of streptozotocin (STZ). Endothelial function in isolated aortic rings was examined; serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were tested by ELISA. The expression of nuclear Factor-κB p65 (NF-κB p65) in aortic tissue was detected by immunohistochemistry. Plasma nitric oxide (NO) was measured by the nitrate reductase method. The expressions of endothelial nitric oxide synthase (eNOS), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and toll-like receptor 4 (TLR4) in aortic tissue were determined by western blot. Key findings The results showed that As-IV significantly improved aortic endothelial function; increased eNOS expression and NO production; and decreased the content of IL-6 and TNF-α and the expressions of VCAM-1, ICAM-1, TLR4, and nuclear NF-κB p65 in vitro and in vivo. In addition, the above mentioned effects of As-IV on human umbilical vein endothelial cells (HUVECs) were similar to TAK-242 (TLR4 inhibitor) and Bay 11-7082 (NF-κB p65 inhibitor). Furthermore, L-NAME (NO synthesis inhibitor) partially abolished the effect of As-IV. Significance As-IV could improve vascular endothelial dysfunction induced by hyperglycemia, and the protective effect of As-IV may be via the TLR4/NF-κB signaling pathway. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Objective Oxidative stress and inflammation are regarded as two important triggers of endothelial dysfunction and play pivotal role in progression of vascular damage associated with cardiac hypertrophy. Our previous studies demonstrated that astragaloside IV (AsIV) could protect against cardiac hypertrophy in rats induced by isoproterenol (Iso), but its effects on the aorta are not known. In present study, we aimed to assess the effects of AsIV on Isoinduced vascular dysfunction. Methods Sprague-Dawley (SD) rats were treated with Iso (10 mg/kg/d) alone or in combination with AsIV (50 mg/kg/d). Results Compared with Isotreated alone, AsIV significantly reduced the ratios of heart weight/body weight and left ventricular weight/body weight. AsIV ameliorated the increased vasoconstriction response to phenylephrine induced by Iso and suppressed superoxide anion generation in rat aorta, increased endothelial nitric oxide synthase (eNOS) dimer/monomer ratio and its critical cofactor tetrahydrobiopterin (BH 4 ) content in aorta as well as the NO production in the serum, reduced the plasmatic peroxynitrite (ONOO–). Moreover, in contrast with Isotreatment alone, AsIV decreased the ratio of nuclear-to-cytosolic protein expression of the NF-κB p65 subunit while enhanced its inhibited protein expression of IκB-α, down-regulated mRNA expression of IL-1β, IL-6 and TNF-α of the aorta. Conclusions The present study suggested that AsIV protects against Isoinduced vascular dysfunction probably via attenuating eNOS uncoupling-mediated oxidative stress and inhibiting ROS-NF-κB pathways. [ABSTRACT FROM AUTHOR]

Calpain-1 activation and oxidative stress are two critical factors contributing to apoptosis of hypertrophic cardiomyocyte. Astragaloside IV (ASIV) exhibits protective effect against various heart diseases. The present study was designed to investigate whether the inhibitory effect of ASIV on isoproterenol (ISO)-induced apoptosis of hypertrophic cardiomyocyte was associated with the anti-oxidation and calpain-1 inhibition. Hypertrophy, apoptosis, mitochondrial oxidative stress and calpain-1 expression were measured in the heart tissue of Sprague–Dawley (SD) rats and H9C2 cells treated with ISO alone or combination with ASIV. The results showed that ASIV attenuated apoptotic rate, increased Bcl-2 expression, decreased Bax expression, ameliorated the integrity of mitochondrial structure and improved mitochondrial membrane potential (MMP). Moreover, ASIV combination reduced both calpain-1 protein expression and calpain activity, down-regulated mitochondrial NOX4 (mito-NOX4) expression, increased activity of mitochondrial superoxide dismutase (mito-SOD) and mitochondrial catalase (mito-CAT) compared to ISO treated alone. The results suggested that ASIV exerted anti-apoptosis effect on ISO-induced hypertrophic cardiomyocyte by attenuating oxidative stress and calpain-1 activation. [ABSTRACT FROM AUTHOR]

Astragaloside IV (AS-IV), the major active constituent purified from Astragalus membranaceus , was previously reported to have protective effects against cardiac dysfunction. However, the underlying mechanism remains unknown. In the present study, we investigated the protective effect of AS-IV on lipopolysaccharide (LPS)-induced cardiac dysfunction and explored the potential mechanism by focusing on miRNA-1 (miR-1) at the animal and cellular levels. A series of methods were used, including echocardiography, flow cytometry, ELISA, immunofluorescence, transmission electron microscopy, RT-PCR, and western blotting. The results showed that both AS-IV and the miR-1 inhibitor improved cardiac dysfunction, reduced heart injury, inhibited apoptosis and autophagy, and regulated the expression of calcium- and mitochondrial energy metabolism-related proteins in the heart tissue of rats treated with LPS. Importantly, AS-IV downregulated the expression of miR-1 mRNA in heart tissue. All effects of AS-IV were at least partly abolished by miR-1 mimics. In the in vitro study, both AS-IV and the miR-1 inhibitor inhibited apoptosis and autophagy and regulated the expression of calcium- and mitochondrial energy metabolism-related proteins in heart cells treated with LPS. Similarly, AS-IV downregulated the expression of miR-1 mRNA in heart cells. All effects of AS-IV on cells were at least partly abolished by miR-1 mimics. Furthermore, miR-1 mimics exhibited effects similar to LPS both in animal and cellular studies. Taken together, these results suggest that AS-IV protects against LPS-induced cardiac dysfunction by inhibiting calcium-mediated apoptosis and autophagy by targeting miR-1, highlighting a new mechanism for the therapeutic effect of AS-IV on cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Vascular endothelial cells act as a selective barrier between circulating blood and vessel wall and play an important role in the occurrence and development of cardiovascular diseases. Astragaloside IV (As-IV) has a protective effect on vascular endothelial cells, but its underlying mechanism remains unclear. This study is aimed at investigating the effect of As-IV on endothelial dysfunction (ED). Male Sprague-Dawley (SD) were injected intraperitoneally with 65 mg/kg streptozotocin (STZ) to induce diabetes and then administered orally with As-IV (40, 80 mg/kg) for 8 weeks. Vascular function was evaluated by vascular reactivity in vivo and in vitro. The expression of calpain-1 and eNOS in the aorta of diabetic rats was examined by western blot. NO production was measured using nitrate reductase method. Oxidative stress was determined by measuring SOD, GSH-px and ROS. Our results showed that As-IV administration significantly improved diabetes associated ED in vivo , and both NAC (an antioxidant) and MDL-28170 (calpain-1 inhibitor) significantly attenuated hyperglycemia-induced ED in vitro. Meanwhile, pretreatment with the inhibitor l-NAME nearly abolished vasodilation to ACh in all groups of rats. Furthermore, As-IV increased NO production and the expression of eNOS in the thoracic aorta of diabetic rats. In addition, the levels of ROS were significantly increased, and the activity of SOD and GSH-px were decreased in diabetic rats, while As-IV administration reversed this change in a concentration-dependent manner. These results suggest that As-IV improves endothelial dysfunction in thoracic aortas from diabetic rats by reducing oxidative stress and calpain-1. [ABSTRACT FROM AUTHOR]