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


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-1(pos)/KDR(pos) 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-1alpha mRNA and protein expression. The ACE inhibitor but not TAC improved the migratory capacity of DiLDL(pos) 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 CD31(pos) cells to cardiomyocytes. Bone marrow transplantation studies revealed that TAC increased the percentage of bone marrow-derived GFP(pos) 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.
Müller
Patrick
P
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. patrick.mueller@uks.eu
Kazakov
Andrey
A
Jagoda
Philippe
P
Semenov
Alexander
A
Böhm
Michael
M
Laufs
Ulrich
U
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D006984:Hypertrophy / Q000378:metabolism / Q000517:prevention & control; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017257:Ramipril / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017257:Ramipril