The Effect Of Radix Astragali And Its Monomer Astragaloside â…£ On Cardiac Damage In Metabolic Syndrome And Hypertension

Effect of Radix Astragali on the Expressions of Angiotensin 1-7 Receptor in Myocardium of Metabolic Syndrome RatsObjective:To clarify the anti-oxidative role of Radix Astragali and its effects on the angiotensin (Ang) 1-7 specific receptor, Mas, in metabolic syndrome (MS) rats.Methods:A total of 160 male SD rats were divided into three groups:nomal control group (NC), MS group, MS+Radix Astragali group (MS+RA,6 mg/kg/day in gavage) and MS+high dose Radix Astragali group (MS+HRA,10 mg/kg/day in gavage). The two-kidney, one-clip method with high-fat diet and fructose water was constructed to set up the MS model. After four weeks treatment, the hemodynamic and echocardiographic parameters were used to assess the left ventricular functions. Plasma and myocardial Ang Ⅱ, malondialdehyde and superoxide demutase (SOD) levels were measured with radioimmunoassay. The protein levels of Mas, angiotensin converting enzyme (ACE) and ACE2 were detected by western blot analysis.Results:Compared with NC group, the systolic and diastolic pressure, body weight, fasting glucose, fasting insulin, triglycerides, free fatty acid, Ang Ⅱ and myocardial malondialdehyde level(P<0.05) of MS, MS+RA and MS+HRA were significantly increased (P<0.05), while myocardial SOD activity was decreased (P<0.05).The plasma Ang Ⅱ and myocardial malondialdehyde level of MS+RA and MS+HRA groups were lower than MS group (P=0.001, 0.017), while myocardial SOD activity was increased.Hemodynamic parameters showed that left ventricular internal pressure -dp/dt of MS+RA group wsa higher than MS group (P=0.037, 0.033).ACE protein expression in myocardial tissue of MS group was increased than NC group,while ACE2 and Mas receptor expression were decreased (all P<0.05).Compared with MS group,ACE protein expression in myocardial tissue was decreased,while ACE2 and Mas receptor expression were increased in MS+RA and MS+HRA groups (all P<0.05).Conclusions:Astragali can increase the ACE2 and Mas receptor expressions through anti-oxidative effects. This has implications for new therapeutic in metabolic syndrome.Astragaloside Ⅳ Improved Left Ventricular Diastolic Dysfunction in Metabolic Syndrome Rats through eNOS/NO/cGMP PathwayObjective:Metabolic syndrome (MS) is a major risk factor for heart failure, initially manifesting as diastolic dysfunction. In this study, the effects and mechanisms of astragaloside Ⅳ (AST) were investigated on high fructose/high fat diet (HFFD)-induced MS rats.Methods:The rat MS model was established by feeding HFFD for 24 weeks. Rats were assigned to four groups:normal control group, MS group, MS+AST 0.5 (0.5 mg/kg, i.p.) group, and MS+AST 2 (2 mg/kg, i.p.) group. Hemodynamic and echocardiographic parameters were used to assess left ventricular functions. Left ventricular tissue and plasma samples were collected for biochemical and molecular analysis.Results:The HFFD fed rats exhibited hypertriglyceridaemia, high blood glucose, hyperinsulinemia, elevated blood pressure, weight gain, and diastolic dysfunction. AST improved diastolic dysfunction without any effects on systolic function in the MS rats. In the present study, experimental results showed that nitric oxide (NO) production and superoxide dismutase (SOD) levels decreased, while levels of malondialdehyde (MDA) increased in left ventricular cardiomyocytes of MS rats. After treatment with AST in MS rats, cardiac MDA was attenuated, and NO production and SOD levels were dose-dependently improved. The highest AST (2.0 mg/kg) dose increased cyclic guanosine monophosphate (cGMP) production in the myocardium. At the mean time, total endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) expression had no significant changes. Compared with normal control rats, the eNOS dimer was decreased in HFFD-induced MS rats. Both low and high dose AST treatments restored eNOS dimer expression of the myocardium in MS rats.Conclusions:The present study demonstrated that AST ameliorated oxidative stress damage and metabolic abnormalities in HFFD-induced MS rats. The antioxidant properties of AST and its protective mechanisms of left ventricular diastolic function worked through the eNOS/NO/cGMP pathway.Astragaloside IV Improves Left Ventricular Diastolic Dysfunction Through Increasing Phosphorylated-Endothelial Nitric Oxide SynthaseObjective:There are no specific treatments for diastolic dysfunction, partly because of a relative lack of a mechanism understanding of this disorder. Recently, we showed that diastolic dysfunction was associated with NOS uncoupling, cardiac oxidative stress and S-glutathionylation of myosin binding protein C (MyBP-C). Astragaloside IV, which is a saponin, has been reported to enhance the activity of eNOS by increasing the scavenging of reactive oxygen species and NO production. We hypothesized that oxidative stress may decrease eNOS phosphorylation and result in diastolic dysfunction in DOCA-salt mice,which would be reversed by ASI treatment.Methods:We used the deoxycorticosterone acetate(DOCA)-salt mouse model. Mice were divided into four groups,SHAM and DOCA control mice received sterile water, and other two groups SHAM+AST and DOCA+AST that received AST treatment by intraperitoneal injection 0.02mg/kg/day for 7days. Diastolic function were assessed by echocardiography and lonOptix. eNOS monomer,dimer and phosphorylation were assayed with western blot analysis. High performance liquid chromatography (HPLC) analysis was used to measure cardiac superoxide anion and biopterins.Results:DOCA mice exhibited diastolic dysfunction that was reversed after AST treatment(E’/A’:SHAM vs. DOCA 1.27±0.13 vs.0.62±0.07 p<0.001; DOCA vs. DOCA+AST 0.62±0.07 vs.1.27±0.29 p=0.002). The DOCA mice showed increased superoxide production and reduced NO production alleviating by AST (p=0.049 and p=0.04). Our results showed that eNOS dimers, eNOS-S1177 and eNOS-T495 was significantly decreased in DOCA-salt mice compared with SHAM mice. eNOS-S1177 increased in DOCA+AST mice compared with untreated DOCA-salt mice (p=0.026), however AST had no effect on phosphorylated eNOS-T495.MyBP-C S-glutathionylation increased after AST treatment in DOCA+AST mice compared with DOCA-salt hyertensive mice(p=0.046).Conclusions:The decrease of eNOS dimerization and phosphorylation are correlated with diastolic dysfunction, which reverse by AST in DOCA-salt mice. The effects of AST for MyBP-C glutathionylation and eNOS phosphorylation preserve cardiac relaxation via its anti-oxidative properties.The Mechanism of the Astragaoloside IV Effect on the Arrhythmia and Cardiac Function in Hypertensive Heart disease MiceObjective:HF is associated with increased arrhythmic risk, at least in part because of action potential prolongation and triggered activity. Abnormal Ca2+ handling is thought to underlie in triggered activity, Ca2+ cylcling is influenced by NCXland CAMKII, known to be active in HF and contribute to arrhythmic risk. Therefore, we tested whether cytoplasmic and mitochondrial Ca2+ flux contributed to EADs in HF and whether EADs in HF were enhanced by astragaloside IV effects on Ca2+ handling.Methods:A model of nonischemic cardiomyopathy was induced in C57BL/6 mice by hypertension after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt water substitution. Electrocardiographic telemetry recording was used to monitor arrhythmias from DOCA mice and sham mice at 18 weeks of age and 6 weeks after DOCA operation. Action potentials (APs) were recorded by perforated current-clamp in isolated mouse ventricular cells. Potassium and L-type Ca2+ currents were measured by whole cell voltage-clamp. Changes in cytoplasmic and mitochondrial Ca2+ were determined by fluorescent imaging using Fluo-4 and Rhod-2, respectively, in isolated ventricular cells.Results:The left ventricular ejection fraction was significantly reduced (43.91±6.85% vs. 55.57±4.48%, p<0.05) in DOCA mice after 6 weeks unilateral nephrectomy, DOCA pellet implantation. Compared with control APs, myopathic cardiomyocytes showed an increase in the AP duration at 90% repolarization (APD90) from 83 ± 21 to 242 ± 45 ms (p<0.01, Fig2 A&B). Seventy-five percent of DOCA ventricular myocytes showed EADs compared with 17% of sham myocytes (p<0.05). After astragaloside Ⅳ treatment, in the in firstly 30 second, the myocytes was obviously prolong in the AP duration at 90% repolarization, and then after 3-5 minutes, the APD90 was significantly shorted than before treatment both in SHAM and DOCA myocytes. Myopathic ventricular cells showed an augmentation of depolarizing L-type Ca2+ currents. Additionally, peak currents and steady state K+ currents were reduced in DOCA mice (p<0.05). Compared with the control cells, the peak amplitudes (F/F0) of cytoplasmic Ca2+ transients were reduced by 33%(3.82 ± 0.35 vs.2.56 ± 0.38,p<0.05) in myopathic ventricular cells.Treatment with AST could increased 2 times peak amplitudes (F/F0) of cytoplasmic Ca2+ transients than before treatment.Conclusions:Sustained hypertension caused nonischemic cardiomyopathy in DOCA, it also showed spontaneous arrhythmias. Ca2+ handling plays an important role in early afterdepolarizations seen with nonischemic cardiomyopathy and may represent a noveltherapeutic target to reduce arrhythmic risk in this condition.Astragaoloside IV treatment may improve cardiac funtion and arrhythmia by increased Ca2+ transients and decreased mitochondrial ROS.