The renin inhibitor aliskiren upregulates pro-angiogenic cells and reduces atherogenesis in mice.
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 ± 14%) and spleen-derived DiLDL/lectin positive PAC (180 ± 21%). Migratory capacity of PAC was increased to 165 ± 16%. In cultured human PAC, aliskiren dose-dependently increased the number of colony forming units to 152 ± 9% (1 μmol/l) and 187 ± 7% (10 μmol/l), which was prevented by the eNOS inhibitor LNMA. H₂O₂-induced apoptosis of cultured human PAC was reduced to 77 ± 23%. In Apo E(-/-) mice, aliskiren reduced atherosclerotic plaque area in the aortic sinus by 58 ± 4%. Circulating Sca-1/VEGFR-2 positive PAC were upregulated to 180 ± 25% and migratory capacity of PAC was increased to 127 ± 7%. Aliskiren reduced vascular NADPH oxidase activity to 41.6 ± 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 ± 30% and their migratory capacity to 214 ± 24%. Aliskiren increased number and function of PAC in mice and prevented atherosclerotic lesion formation. The effects were observed independent of blood pressure lowering.
Pöss
Janine
J
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrbergerstr., 66421, Homburg, Saar, Germany. Janine.poess@gmx.de
Werner
Christian
C
Lorenz
Dominik
D
Gensch
Christoph
C
Böhm
Michael
M
Laufs
Ulrich
U
D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D055104:Infusions, Subcutaneous; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D012083:Renin / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000092502:Renin Inhibitors
D000577:Amides; D043925:Angiogenesis Inducing Agents; D000950:Antigens, Ly; D001057:Apolipoproteins E; D005650:Fumarates; D008565:Membrane Proteins; D019255:NADPH Oxidases; D012083:Renin; D040301:Vascular Endothelial Growth Factor Receptor-2; D000092502:Renin Inhibitors; C074650:Ly6a protein, mouse; C446481:aliskiren