Possible Involvement of "Phosphatidylinositol-3 kinase and endothelial nitric oxide synthase' in experimental obesity induced vascular endothelium dysfunction.

This study was designed to investigate the possible role of Phosphatidylinositol-3 kinase (PI3K) and endothelial nitric oxide synthase (eNOS) in obesity-induced vascular endothelium dysfunction. Wistar rats were fed high fat diet (HFD) for 12 weeks to induce obesity. HFD induce obesity significantly increased parameters employed viz body weight, basal metabolic index (BMI), total fat pad and lipid profile. Furthermore vascular endothelial dysfunction was assessed in terms of decrease in endothelium dependent relaxation and serum nitrate/nitrite level and increase in mean arterial blood pressure. Atorvastatin (30mg/kg,i.p.) was employed in the present study as standard drug to improve vascular endothelial dysfunction. YS-49 (1.6 mg/kg, i.p.) a specific activator of PI3K and atorvastatin in obese rats significantly improves the lipid profile and markedly improved acetylcholine induced endothelium dependent relaxation, serum nitrite/nitrate concentration and mean arterial blood pressure. However, this ameliorative effect of YS-49 has been prevented by L-NAME (25 mg/kg, i.p.), an inhibitor of eNOS. Further wortmannin (100μg/kg, i.p.),a specific PI3K inhibitor improves the anthropometric parameters and lipid profile but did not show any significant effect on acetylcholine dependent relaxation, serum nitrate/nitrite level and mean arterial blood pressure. Therefore, it may be concluded that PI3K and eNOS pathway is dysregulated in obesity induced vascular endothelial dysfunction and YS-49, a PI3K activator improves vascular endothelial function in eNOS and nitric oxide dependent manner. Abbreviations (Ach): Acetylcholine, (Ang-II): Angiotensin II, (BMI): Body Mass Index, (Enos): Endothelial Nitric Oxide, Synthase, (HO-1): Heme Oxygenase, (Kcl): Pottesium Cloride, (MAP): Mean Arterial Pressure, (NO): Nitric Oxide, (PI3K): Phosphatidylinositol 3-Kinase, (SNP ): Sodium Nitroprusside, (VED): Vascular Endothelium Dysfunction

Ameliorative effect of daidzein: A caveolin-1 inhibitor in vascular endothelium dysfunction induced by ovariectomy.

Estrogen deficiency was produced in female Sprague-Dawley rats by surgical removal of both the ovaries and these animals were used 4 weeks later. Endothelium-dependent and endothelium-independent relaxations due to acetylcholine and sodium nitroprusside were observed respectively, in isolated rat thoracic aortic ring preparation. Extent of lipid peroxidation was measured by estimating serum TBARS. Integrity of vascular endothelium was assessed using hematoxylin and eosin staining. Generation of nitric oxide was measured indirectly, by estimating serum and urinary nitrite/nitrate concentration. Ovariectomy produced significant vascular endothelial dysfunction, measured in terms of reduced acetylcholine-induced endothelium-dependent vasorelaxation, serum and urinary nitrite/nitrate concentration and impairment of integrity of vascular endothelium. Administration of daidzein (0.2 mgkg-1day-1, sc 0.4 mgkg-1day-1, sc and 0.8 mgkg-1day-1, sc) and Atorvastatin (30 mgkg-1day-1, po Positive Control) for one week markedly improved vascular endothelial dysfunction due to increase in nitric oxide bioavailability perhaps by inhibiting caveolin-1 and activation of PI3K-AKT pathway.