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The renin inhibitor aliskiren upregulates pro-angiogenic cells and reduces atherogenesis in mice

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Abstract

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.

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Acknowledgments

We thank Ellen Becker, Simone Jäger and Lena Brachmann for their excellent technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (UL, MB) and the Universität des Saarlandes (HOMFOR, JP).

Conflict of interest

The Universität des Saarlandes received an unrestricted minor grant from Novartis.

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  1. Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrbergerstr., 66421, Homburg, Saar, Germany

    Janine Pöss, Christian Werner, Dominik Lorenz, Christoph Gensch, Michael Böhm & Ulrich Laufs

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  1. Janine Pöss
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Pöss, J., Werner, C., Lorenz, D. et al. The renin inhibitor aliskiren upregulates pro-angiogenic cells and reduces atherogenesis in mice. Basic Res Cardiol 105, 725–735 (2010). https://doi.org/10.1007/s00395-010-0120-5

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  • DOI: https://doi.org/10.1007/s00395-010-0120-5

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