The endothelial response to diabetes reveals a protective role for galectin-3 in diabetic vasculopathy and glucose metabolism

Abstract

Type II Diabetes is associated with an increased risk of cardiovascular disease primarily due to a damaged or dysfunctional endothelium. To characterize the endothelial dysfunction in diabetes, we surveyed the transcriptional responses in the vascular endothelia of mice receiving a high-fat diet. Mice were fed a 60% fat calorie diet (HFD) for up to 8 weeks to induce a state of insulin resistance; controls were fed normal chow. Transcriptional analysis of the aortic and skeletal muscle endothelium of these mice performed using whole genome microarrays identified galectin-3, a carbohydratebinding lectin, as a highly dysregulated transcript. The mRNA for galectin-3 was 16-fold more abundant in the aortic endothelium after 4 weeks of HFD, and this same level of dysregulation was observed in the muscle endothelium after 8 weeks. LGALS3 protein was similarly upregulated in the endothelium as confirmed by immunofluorescence. The level of circulating LGALS3 in the serum of HFD mice was elevated vs. controls (91 + 12 vs. 34 + 3 ng/mL, P < 0.001) and positively correlated with the degree of insulin resistance (R2=0.92, P < 0.0001), suggesting its potential for use as a biomarker for the vascular complications of diabetes. Lgals3-deficient mice (KO) fed a HFD for 8 weeks display impaired glucose tolerance and exacerbated hyperglycemia compared to WT (231 + 35 vs. 185 + 30 mg/dL, P = 0.001). Transcriptional analysis of the aortic and muscle endothelial response to HFD of KO mice vs. WT mice revealed differential dysregulation of transcripts involved in glucose uptake, insulin signaling, atherosclerosis, and coagulation. One highly downregulated transcript in both the macro-and microvasculture of the KO by 4-and 16-fold after high-fat feeding was the glucose transporter, Glut4. Immunofluorescence confirmed the decreased abundance of GLUT4 protein in the endothelium and muscle of the diabetic KO compared to WT. Upregulated expression of coagulation factors in the aortic endothelium and decreased prothrombin time revealed increased coagulation activity occurring in the diabetic KO. This data suggests that galectin-3 is involved in regulating glucose metabolism and its upregulation in the diabetic vasculature may serve a protective role against the cardiovascular complications of diabetes.