Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase.
BACKGROUND
Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI.


RESULTS
Wild-type (WT) and eNO synthase (eNOS)-/- mice with extensive anterior MI were randomized to treatment with vehicle (V) or atorvastatin (Ator, 50 mg/kg QD by gavage) for 4 weeks starting on day 1 after MI. Ator markedly improved endothelium-dependent, NO-mediated vasorelaxation; mobilization of endothelial progenitor cells; and myocardial neovascularization of the infarct border in WT mice after MI while having no effect in eNOS-/- mice. LV dysfunction and interstitial fibrosis were markedly attenuated by Ator in WT mice, whereas no effect was observed in eNOS-/- mice after MI. Importantly, Ator significantly increased the survival rate during 4 weeks after MI in WT mice (Ator versus V, 80% versus 46%; P<0.01, n=75) but not in eNOS-/- mice (43% versus 48%; NS, n=42).


CONCLUSIONS
These findings suggest that increased eNO availability is required for statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, LV dysfunction, interstitial fibrosis, and survival after MI. eNO bioavailability after MI likely represents an important therapeutic target in heart failure after MI and mediates beneficial effects of statin treatment after MI.
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany. Landmesser.Ulf@mh-hannover.de.
Ulf
U
Landmesser
Niels
N
Engberding
Ferdinand H
FH
Bahlmann
Arnd
A
Schaefer
Antje
A
Wiencke
Andre
A
Heineke
Stephan
S
Spiekermann
Denise
D
Hilfiker-Kleiner
Christian
C
Templin
Daniel
D
Kotlarz
Maja
M
Mueller
Martin
M
Fuchs
Burkhard
B
Hornig
Hermann
H
Haller
Helmut
H
Drexler
D000818:Animals; D000069059:Atorvastatin; D001682:Biological Availability; D002196:Capillaries / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects; D003097:Collateral Circulation / Q000187:drug effects*; D004351:Drug Resistance / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D005355:Fibrosis; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D009569:Nitric Oxide; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse