| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 104 === Aliskiren is a direct renin inhibitor which is suggested to modify proangiogenic cells in addition to lower blood pressure. Given that angiogenesis is impaired in the presence of diabetes mellitus, we would like to investigate whether and how aliskiren enhances endothelial progenitor cells (EPCs) and improves ischemic-induced neovasculogenesis by an effect independent of blood pressure reduction in diabetic animals.
Streptozotocin-induced diabetic mice were administered with either aliskiren (5 or 25 mg/kg/day) using an osmotic pump or hydralazine (2 or 10 mg/kg/day) given in drinking water for two weeks prior to a hind-limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs respectively. EPC function and signal pathways after aliskiren treatment were also studied.
In streptozotocin-induced diabetic mice, aliskiren enhanced the recovery of limb perfusion and capillary density, increased the number of circulating Sca-1+/Flk-1+ EPC-like cells, and elevated the levels of the plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α in a dose-dependent manner, whereas there were no such effects in hydralazine-treated mice. Intraperitoneal administration of anti-SDF-1 neutralizing monoclonal antibody abolished the effects of aliskiren. In the in vitro study, aliskiren dose-dependently improved the function and increased both VEGF and SDF-1α expression of EPCs from type II diabetic patients. Transfection with VEGF siRNA significantly reduced aliskiren-induced SDF-1α expression. Furthermore, (pro)rennin receptor siRNA transfection impared aliskiren-induced VEGF and SDF-1 expression.
In conclusion, independent of the reduction of blood pressure, aliskiren enhanced ischemia-induced neovasculogenesis in a dose-dependent manner via VEGF/SDF-1α related mechanisms in diabetic mice. Moreover, aliskiren improved human EPC function probably via the (pro)renin receptor and VEGF/SDF-1α related signal pathways.
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