on September 20, 2004
Circulation. 2004
Published online before print September 20, 2004, doi: 10.1161/01.CIR.0000143232.67642.7A
Published online before print September 20, 2004, doi: 10.1161/01.CIR.0000143232.67642.7A
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Submitted on March 16, 2004
From Abteilung Kardiologie und Angiologie (U.L., N.E., A.S., A.W., A.H., S.S., D.H.-K., C.T., D.K., M.M., M.F., B.H., H.D.) and Abteilung Nephrologie (F.H.B., H.H.), Medizinische Hochschule Hannover, Hannover, Germany. * To whom correspondence should be addressed. E-mail: Landmesser.Ulf{at}mh-hannover.de.
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. Methods and 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.
Revised on May 23, 2004
Accepted on July 7, 2004
Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase
Ulf Landmesser MD*,
Key words: endothelium • nitric oxide synthase • statins • myocardial infarction • heart failure
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