Chen Lei-Lei, Yin Hang, Huang Jun
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China.
Cardiovasc Pathol. 2007 Jul-Aug;16(4):221-30. doi: 10.1016/j.carpath.2007.02.007. Epub 2007 May 11.
Endothelial nitric oxide synthase and nitric oxide have been implicated in protection against myocardial ischemia injury. However, the angiogenic effect of endothelial nitric oxide synthase on infarcted myocardium and the role of tumor growth factor beta1 signaling in cardiac remodeling mediated by endothelial nitric oxide synthase/nitric oxide have not yet been elucidated.
Human endothelial nitric oxide synthase gene in an adenovirus vector was delivered locally into rat heart 4 days prior to the induction of myocardial infarction by left anterior descending coronary artery ligation. Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and neovascularization was identified immunohistochemically.
Endothelial nitric oxide synthase gene transfer significantly reduced infarct size and improved cardiac contractility and left ventricular diastolic function at 24 h after myocardial infarction. In addition, endothelial nitric oxide synthase significantly reduced myocardial-infarction-induced cardiomyocyte apoptosis. Activation of tumor growth factor beta1 and Smad-2 after myocardial infarction was also dramatically reduced by endothelial nitric oxide synthase. Moreover, the deterioration of both systolic and diastolic functions, in conjunction with thin left ventricular remodeling at 7 days after myocardial infarction, was prevented by endothelial nitric oxide synthase. Capillary density, as identified by alpha-smooth muscle actin immunostaining, was significantly increased in the infarcted myocardium after endothelial nitric oxide synthase transfer compared with myocardial infarction control. All cardioprotective effects of endothelial nitric oxide synthase were blocked by N(omega)-nitro-l-arginine methyl ester administration, indicating a nitric-oxide-mediated event.
These results demonstrate that the endothelial nitric oxide synthase/nitric oxide system provides cardiac protection after myocardial infarction injury through inhibition of cardiac apoptosis, stimulation of neovascularization, and suppression of tumor growth factor beta1/Smad-2 signaling.
内皮型一氧化氮合酶和一氧化氮被认为具有保护心肌免受缺血损伤的作用。然而，内皮型一氧化氮合酶对梗死心肌的血管生成作用以及肿瘤生长因子β1信号通路在内皮型一氧化氮合酶/一氧化氮介导的心脏重塑中的作用尚未阐明。
在通过结扎左冠状动脉前降支诱导心肌梗死前4天，将携带人内皮型一氧化氮合酶基因的腺病毒载体局部注入大鼠心脏。通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法检测心肌细胞凋亡，并用免疫组织化学法鉴定新生血管形成。
内皮型一氧化氮合酶基因转移显著减小了心肌梗死后24小时的梗死面积，改善了心脏收缩功能和左心室舒张功能。此外，内皮型一氧化氮合酶显著减少了心肌梗死诱导的心肌细胞凋亡。内皮型一氧化氮合酶还显著降低了心肌梗死后肿瘤生长因子β1和Smad-2的激活。此外，内皮型一氧化氮合酶预防了心肌梗死后7天时收缩和舒张功能的恶化以及左心室壁变薄的重塑。与心肌梗死对照组相比，内皮型一氧化氮合酶基因转移后梗死心肌中通过α-平滑肌肌动蛋白免疫染色鉴定的毛细血管密度显著增加。内皮型一氧化氮合酶的所有心脏保护作用均被N（ω）-硝基-L-精氨酸甲酯给药所阻断，表明这是一个一氧化氮介导的事件。
这些结果表明，内皮型一氧化氮合酶/一氧化氮系统通过抑制心脏细胞凋亡、刺激新生血管形成和抑制肿瘤生长因子β1/Smad-2信号通路，在心肌梗死损伤后提供心脏保护。
