Effects of GDF11 on endothelium-dependent vasodiation function of aorta in ApoE-/- diabetic mice

Abstract

Objective To explore the effects of growth differentiation factor 11 (GDF11) on endothelium-dependent vasodilation function of aorta in apolipoprotein E-Null (ApoE-/-) diabetic mice and to investigate the mechanisms. Methods Ten of the 40 healthy male ApoE-/- mice at 4-week age were selected as normal control group according to random number method and received basic diet, whereas the other 30 mice were fed with high-fat diet for 4 weeks and then treated with streptozotocin intraperitoneal injection (50 mg/kg) for 5 days to induce type 2 diabetes mellitus (T2DM). Diabetes was successfully induced in twenty mice which were then randomly divided into GDF11 group (0.1 mg·kg-1·d-1 intraperitoneal injection, n=10) and T2DM control group (T2DM group, equivalent phosphate buffered saline, n=10) according to random number method. After 4 weeks of intervention, fasting plasma glucose, fasting plasma insulin, HbA1c and serum GDF11 were measured respectively. Homeostasis model assessment-insulin sensitive index (HOMA-ISI) was calculated. The relaxation response and nitric oxide levels were detected in isolated aorta of mice. Acetylcholine (Ach)-induced endothelium-dependent vasodilation and sodium nitroprusside (SNP) -induced endothelium-independent vasodilation were measured in aortas for estimating endothelial function. Endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (P-eNOS) and Smad2/3, phosphorylated Smad2/3 (P-Smad2/3) were measured by Western blotting in isolated aorta of mice. Results Compared with NC group, fasting plasma glucose, fasting plasma insulin, and HbA1c were significantly increased, meanwhile HOMA-ISI, serum GDF11 concentration and Ach-dependent relaxation response were significantly reduced in T2DM group; compared with T2DM group, all markers mentioned above were improved in GDF11 group (F=70.923-675.430, all P 0.05). Compared with NC group, nitric oxide, P-eNOS, P-Smad2/3 were significantly decreased in T2DM group, but indexes mentioned above were all increased in GDF11 group (F=40.120-148.060, all P<0.01). Conclusion GDF11 improves endothelium-dependent vasodilation function in ApoE-/- diabetic mice by enhancing nitric oxide synthesis and Smad2/3 signaling pathways. Key words: Growth differentiation factor 11; Type 2 diabetes mellitus; Endothelium-dependent vasodilation; Nitric oxide