Buys Emmanuel S, Raher Michael J, Blake Sarah L, Neilan Tomas G, Graveline Amanda R, Passeri Jonathan J, Llano Miguel, Perez-Sanz Teresa M, Ichinose Fumito, Janssens Stefan, Zapol Warren M, Picard Michael H, Bloch Kenneth D, Scherrer-Crosbie Marielle
Cardiac Ultrasound Laboratory, 55 Fruit Street, Boston, MA 02115-2696, USA.
Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H620-7. doi: 10.1152/ajpheart.01236.2006. Epub 2007 Apr 6.
Although nitric oxide synthase (NOS)3 is implicated as an important modulator of left ventricular (LV) remodeling, its role in the cardiac response to chronic pressure overload is controversial. We examined whether selective restoration of NOS3 to the hearts of NOS3-deficient mice would modulate the LV remodeling response to transverse aortic constriction (TAC). LV structure and function were compared at baseline and after TAC in NOS3-deficient (NOS3(-/-)) mice and NOS3(-/-) mice carrying a transgene directing NOS3 expression specifically in cardiomyocytes (NOS3(-/-TG) mice). At baseline, echocardiographic assessment of LV dimensions and function, invasive hemodynamic measurements, LV mass, and myocyte width did not differ between the two genotypes. Four weeks after TAC, echocardiographic and hemodynamic indexes of LV systolic function indicated that contractile performance was better preserved in NOS3(-/-TG) mice than in NOS3(-/-) mice. Echocardiographic LV wall thickness and cardiomyocyte width were greater in NOS3(-/-) mice than in NOS3(-/-TG) mice. TAC-induced cardiac fibrosis did not differ between these genotypes. TAC increased cardiac superoxide generation in NOS3(-/-TG) but not NOS3(-/-) mice. The ratio of NOS3 dimers to monomers did not differ before and after TAC in NOS3(-/-TG) mice. Restoration of NOS3 to the heart of NOS3-deficient mice attenuates LV hypertrophy and dysfunction after TAC, suggesting that NOS3 protects against the adverse LV remodeling induced by prolonged pressure overload.
尽管一氧化氮合酶（NOS）3被认为是左心室（LV）重塑的重要调节因子，但其在心脏对慢性压力超负荷反应中的作用仍存在争议。我们研究了选择性地将NOS3恢复到NOS3基因缺陷小鼠的心脏中是否会调节LV对主动脉缩窄（TAC）的重塑反应。比较了NOS3基因缺陷（NOS3(-/-)）小鼠和携带在心肌细胞中特异性指导NOS3表达的转基因的NOS3(-/-)小鼠（NOS3(-/-TG)小鼠）在基线时以及TAC后的LV结构和功能。在基线时，两种基因型之间的LV尺寸和功能的超声心动图评估、有创血流动力学测量、LV质量和心肌细胞宽度没有差异。TAC后四周，LV收缩功能的超声心动图和血流动力学指标表明，NOS3(-/-TG)小鼠的收缩性能比NOS3(-/-)小鼠更好地得以保留。NOS3(-/-)小鼠的超声心动图LV壁厚度和心肌细胞宽度比NOS3(-/-TG)小鼠更大。这些基因型之间TAC诱导的心脏纤维化没有差异。TAC增加了NOS3(-/-TG)小鼠而非NOS3(-/-)小鼠的心脏超氧化物生成。在NOS3(-/-TG)小鼠中，TAC前后NOS3二聚体与单体的比例没有差异。将NOS3恢复到NOS3基因缺陷小鼠的心脏中可减轻TAC后的LV肥大和功能障碍，这表明NOS3可防止长期压力超负荷诱导的不良LV重塑。
