Landmesser Ulf, Engberding Niels, Bahlmann Ferdinand H, Schaefer Arnd, Wiencke Antje, Heineke Andre, Spiekermann Stephan, Hilfiker-Kleiner Denise, Templin Christian, Kotlarz Daniel, Mueller Maja, Fuchs Martin, Hornig Burkhard, Haller Hermann, Drexler Helmut
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Circulation. 2004 Oct 5;110(14):1933-9. doi: 10.1161/01.CIR.0000143232.67642.7A.
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.
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).
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.
心肌梗死（MI）后及心力衰竭时，内皮型一氧化氮（eNO）生物利用度会严重降低。他汀类药物通过增加eNO生成及减少NO失活来提高eNO生物利用度。因此，我们研究了他汀类药物治疗对MI后eNO生物利用度的影响，并测试了其在MI后内皮祖细胞动员、心肌新生血管形成、左心室（LV）功能障碍、重塑及存活中的作用。
广泛前壁MI的野生型（WT）和eNO合酶（eNOS）基因敲除小鼠于MI后第1天开始随机接受载体（V）或阿托伐他汀（Ator，50mg/kg每日经口灌胃）治疗4周。Ator显著改善了WT小鼠MI后内皮依赖性、NO介导的血管舒张；内皮祖细胞的动员；以及梗死边界的心肌新生血管形成，而对eNOS基因敲除小鼠无影响。Ator显著减轻了WT小鼠的LV功能障碍和间质纤维化，而MI后eNOS基因敲除小鼠未观察到这种作用。重要的是，Ator显著提高了WT小鼠MI后4周的存活率（Ator组与V组，80%对46%；P<0.01，n=75），但对eNOS基因敲除小鼠无此作用（43%对48%；无显著性差异，n=42）。
这些发现表明，MI后他汀类药物诱导的内皮祖细胞动员、心肌新生血管形成、LV功能障碍、间质纤维化及存活改善需要提高eNO生物利用度。MI后eNO生物利用度可能是MI后心力衰竭的一个重要治疗靶点，并介导了MI后他汀类药物治疗的有益作用。
