A0407 Astragaloside IV Reduces Cardiac Oxidation and Improves Left Ventricular Diastolic Dysfunction

Abstract

Objectives: Astragaloside IV (ASI), which is a saponin, has been reported to enhance the activity of eNOS and scavenge reactive oxygen species. We hypothesized that diastolic dysfunction may be associated with reduced eNOS activity that can be reversed by ASI treatment. Methods: We used an established model of isolated diastolic dysfunction caused by deoxycorticosterone acetate (DOCA)-induced mild hypertension. Mice were divided into four groups: sham and DOCA mice with and without ASI treatment. ASI was administrered by intraperitoneal injection of 0.02 mg/kg/day for 7 days. Diastolic function was assessed in vivo by echocardiography and ex vivo in isolated myocytes. eNOS monomer, dimer ratios and phosphorylation were assayed with Western blot analysis. High performance liquid chromatography analysis was used to measure cardiac superoxide anion and biopterins. Results: DOCA mice exhibited diastolic dysfunction (E/E¢:SHAM vs. DOCA 23.90 ± 4.58 vs. 38.83 ± 4.37 p = 0.001) that was reversed after ASI treatment. ASI had no effect on sham animals. Isolated myocytes from the DOCA-salt mice demonstrated impaired relaxation, diastolic sarcomere length and re-lengthening (relaxation constant, τ), which were restored by ASI treatment. The DOCA mice showed increased cardiac superoxide production (2HO-ET level:DOCA vs. DOCA+ASI 0.36 ± 0.19 μmol/mg tissue vs. 0.20 ± 0.05 μmol/mg tissue p = 0.05 and reduced NO production alleviating by ASI. (nitrite/ nitrate content: DOCA vs. DOCA+ASI 2.58 ± 0.49 mmol/mg protein vs. 3.33 ± 0.30 mmol/mg protein p = 0.04). Active eNOS as measured by eNOS dimers andeNOS-S1177 was significantly decreased in DOCA Conclusion: Hypertension induced diastolic dysfunction is associated with increased cardiac oxidation and measures of active eNOS. ASI treatment reversed these changes and improved diastolic dysfunction.