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Cardiovascular Research Advance Access first published online on April 20, 2009
This version [Corrected Proof] published online on May 21, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp123
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

ACE inhibition promotes upregulation of endothelial progenitor cells and neoangiogenesis in cardiac pressure overload

Patrick Müller*,{dagger}, Andrey Kazakov{dagger}, Philippe Jagoda, Alexander Semenov, Michael Böhm and Ulrich Laufs

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany

* Corresponding author. Tel: +49 6841 162 3372; fax: +49 6841 162 3434. E-mail address: patrick.mueller{at}uks.eu

Aims: Inhibition of the angiotensin-converting enzyme (ACE) prevents maladaptive cardiac remodelling. Endothelial progenitor cells (EPC) from the bone marrow contribute to endothelial repair and neovascularization, effects that are potentially important during cardiac remodelling. We hypothesized that ACE inhibitors may exert beneficial effects during pressure-induced myocardial hypertrophy by regulating progenitor cell function.

Methods and results: In C57/Bl6 mice, development of cardiac hypertrophy induced by transaortic constriction (TAC) for 5 weeks was reduced by ramipril, 5 mg/kg p.o., independent of blood pressure lowering. Ramipril prevented TAC-induced apoptosis of cardiac myocytes and endothelial cells. On day 1 after TAC, upregulation of Sca-1pos/KDRpos EPC was observed, which was further increased by ramipril. EPC were persistently elevated in the TAC mice receiving vehicle treatment but not in the ramipril group after 5 weeks. These effects were independent of hypoxia-inducible factor-1{alpha} mRNA and protein expression. The ACE inhibitor but not TAC improved the migratory capacity of DiLDLpos EPC. Increased cardiac afterload induced upregulation of extracardiac neoangiogenesis. This effect was enhanced by ACE inhibition. Ramipril but not TAC markedly increased cardiac capillary density determined by the ratio of CD31pos cells to cardiomyocytes. Bone marrow transplantation studies revealed that TAC increased the percentage of bone marrow-derived GFPpos endothelial cells in the myocardium, and ramipril made this effect more pronounced.

Conclusions: ACE inhibition prevents pressure-induced maladaptive cardiac hypertrophy and increases intra- and extracardiac neoangiogenesis associated with the upregulation of EPC and amelioration of EPC migration. The regulation of progenitor cells from the bone marrow identifies a novel effect of ACE inhibitors during cardiac remodelling.

KEYWORDS Angiotensin-converting enzyme-inhibition; Endothelial progenitor cells; Neoangiogenesis; Transaortic constriction

Time for primary review: 30 days

{dagger} Both authors contributed equally to this study and share first authorship.


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