Dennis Ladage1, Nora Schützeberg2, Theresa Dartsch1, Benjamin Krausgrill1, Marcel Halbach1, Carsten Zobel1, Jochen Müller-Ehmsen3. 1. Laboratory of Muscle Research and Molecular Cardiology, Dept. III of Internal Medicine, University of Cologne, Cologne, Germany. 2. Laboratory of Muscle Research and Molecular Cardiology, Dept. III of Internal Medicine, University of Cologne, Cologne, Germany; Dept. I of Internal Medicine, Technical University of Munich, Klinikum Rechts der Isar, Munich, Germany. 3. Laboratory of Muscle Research and Molecular Cardiology, Dept. III of Internal Medicine, University of Cologne, Cologne, Germany. Electronic address: muller.ehmsen@uni-koeln.de.
Abstract
BACKGROUND: Aldosterone plays a role in hypertension, the pathogenesis of heart failure and vascular injury. However, little information exists about the possible influence of aldosterone on bone marrow derived endothelial progenitor cells (EPC), which are involved in the repair of damaged endothelium. This study was designed to determine the long- term in vivo influence of aldosterone on the number of EPC. METHODS: Male Wistar rats were equipped with a subcutaneous pump which released aldosterone (n=20) or placebo (n=20) over 28 days. The animals were either fed with or without the aldosterone antagonist spironolactone (each n=10). EPC were identified by the uptake of ac-LDL and BS-1. The expression of VEGF-2 receptor, VEGF, HGF, SDF1 and the mineralocorticoid receptor (MR) in EPC was assessed by quantitative PCR. Finally, VEGF concentration was measured in the serum of all animals by ELISA. RESULTS: The total number of EPC was significantly lowered by chronic aldosterone treatment. Spironolactone compensated the effect and lead to a 2-fold increase. While the SDF1 mRNA was not affected by aldosterone, HGF, MR2 and VEGF receptor mRNA were significantly downregulated in EPC. Strikingly spironolactone not only leads to increases in the mRNA expression in hyper-aldosteronemic animals but also exhibited significant increases above the control levels. CONCLUSION: The present data indicate that high levels of aldosterone impair the function and reduce the numbers of EPC and lead to a downregulation of VEGF and the VEGF receptor in vivo. Spironolactone antagonized these effects. MR blockade by spironolactone may therefore represent a future tool to enhance the response to cell based therapy.
BACKGROUND:Aldosterone plays a role in hypertension, the pathogenesis of heart failure and vascular injury. However, little information exists about the possible influence of aldosterone on bone marrow derived endothelial progenitor cells (EPC), which are involved in the repair of damaged endothelium. This study was designed to determine the long- term in vivo influence of aldosterone on the number of EPC. METHODS: Male Wistar rats were equipped with a subcutaneous pump which released aldosterone (n=20) or placebo (n=20) over 28 days. The animals were either fed with or without the aldosterone antagonist spironolactone (each n=10). EPC were identified by the uptake of ac-LDL and BS-1. The expression of VEGF-2 receptor, VEGF, HGF, SDF1 and the mineralocorticoid receptor (MR) in EPC was assessed by quantitative PCR. Finally, VEGF concentration was measured in the serum of all animals by ELISA. RESULTS: The total number of EPC was significantly lowered by chronic aldosterone treatment. Spironolactone compensated the effect and lead to a 2-fold increase. While the SDF1 mRNA was not affected by aldosterone, HGF, MR2 and VEGF receptor mRNA were significantly downregulated in EPC. Strikingly spironolactone not only leads to increases in the mRNA expression in hyper-aldosteronemic animals but also exhibited significant increases above the control levels. CONCLUSION: The present data indicate that high levels of aldosterone impair the function and reduce the numbers of EPC and lead to a downregulation of VEGF and the VEGF receptor in vivo. Spironolactone antagonized these effects. MR blockade by spironolactone may therefore represent a future tool to enhance the response to cell based therapy.