| Description |
Approximately 2 million individuals have type 1 diabetes (T1D) in the United States. Cardiovascular disease is 2-4-fold more prevalent in these patients but the mechanism(s) is unclear. Recently, we showed that the sphingolipid ceramide contributes to arterial dysfunction and hypertension in mice with type 2 diabetes. In the present study we tested the hypothesis that ceramide contributes to endothelium-dependent dysfunction in mice with T1D. Two experiments were performed. In the first, four week old mice were treated with streptozotocin (STZ, 50 mg/kg/day, IP; n=18) or the vehicle sodium citrate (CON, n=18) for 5 days. STZ damages DNA in the beta cells of the pancreas, which are responsible for insulin production. At 21 weeks of age, STZ mice received the ceramide biosynthesis inhibitor myriocin (STZ-MYR; 0.3 mg/kg, IP, n=7) or phosphate buffered saline (STZ-PBS, IP, n=11) every second day for 7 weeks. CON mice received MYR (CON-MYR, n=9) or PBS (CON-PBS, n=9) for the same duration. At 28 weeks of age, blood glucose was greater, and body weight and gonadal fat pad mass were less, in STZ vs. CON mice, regardless of MYR or PBS treatment (all p<0.05). Liver ceramide was elevated (p<0.05) in STZ-PBS mice vs. all other groups. Endothelium-dependent vasorelaxation was impaired (p<0.05) in STZ vs. CON mice, regardless of PBS or MYR treatment, while vascular smooth muscle function was similar among groups. Therefore, even though elevated ceramide content in STZ-PBS mice was lowered in STZ-MYR animals, endothelial dysfunction persisted. These results suggest that ceramide is not the most important contributor to endothelial dysfunction in mice with T1D. In the second study, 7-week old mice were treated with STZ or CON. Concurrent with this, subsets of each group were treated for 7-weeks with MYR or PBS. At 14 weeks four groups were studied i.e., CON-PBS (n=10), CON-MYR (n=12), STZ-PBS (n=12), and STZ-MYR (n=12). Blood glucose was greater, and body weight and gonadal fat pad mass were less, in STZ vs. CON mice, regardless of MYR or PBS treatment. Surprisingly, liver ceramide and vascular function were similar among groups. These results indicate that the metabolic milieu evoked by 7-weeks of T1D was not capable of elevating tissue ceramide or evoking arterial dysfunction. |
