科研之友
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摘要
Sca-1 and VEGFR-2 positive pro-angiogenic cells (PAC) predict outcome of patients with vascular disease. Activation of the renin-angiotensin-aldosterone system impairs PAC function. The effects of the direct renin inhibitor aliskiren on PAC numbers and function are not known. Treatment of C57Bl/6 mice and Apo E(-/-) mice on high-cholesterol diet with aliskiren, 25 mg/kg/day s.c. for 3-6 weeks, reduced systolic and diastolic blood pressure by -11.5 and -13.7% compared to vehicle. Aliskiren increased Sca-1/VEGFR-2 positive PAC in the blood (159 +/- A 14%) and spleen-derived DiLDL/lectin positive PAC (180 +/- A 21%). Migratory capacity of PAC was increased to 165 +/- A 16%. In cultured human PAC, aliskiren dose-dependently increased the number of colony forming units to 152 +/- A 9% (1 mu mol/l) and 187 +/- A 7% (10 mu mol/l), which was prevented by the eNOS inhibitor LNMA. H(2)O(2)-induced apoptosis of cultured human PAC was reduced to 77 +/- A 23%. In Apo E(-/-) mice, aliskiren reduced atherosclerotic plaque area in the aortic sinus by 58 +/- A 4%. Circulating Sca-1/VEGFR-2 positive PAC were upregulated to 180 +/- A 25% and migratory capacity of PAC was increased to 127 +/- A 7%. Aliskiren reduced vascular NADPH oxidase activity to 41.6 +/- A 6.7%. Despite similar blood pressure lowering, treatment with hydralazine (25 mg/kg/day) did not significantly influence atherogenesis or PAC. Treatment of C57Bl/6 mice with a lower dose of aliskiren (15 mg/kg/day) did not affect blood pressure but increased cultured DiLDL/lectin positive PAC to 229 +/- A 30% and their migratory capacity to 214 +/- A 24%. Aliskiren increased number and function of PAC in mice and prevented atherosclerotic lesion formation. The effects were observed independent of blood pressure lowering.
- 出版日期2010-11
