Elrod John W, Greer James J M, Bryan Nathan S, Langston Will, Szot Jeffrey F, Gebregzlabher Henock, Janssens Stefan, Feelisch Martin, Lefer David J
Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1517-23. doi: 10.1161/01.ATV.0000224324.52466.e6. Epub 2006 Apr 27.
The protective effect of NO synthase-3 (eNOS)-derived NO in limiting myocardial ischemia-reperfusion (MI-R) injury is well established. We reported previously that systemic genetic overexpression of eNOS attenuates MI-R injury. The purpose of the current study was to investigate tissue-specific genetic overexpression of the human eNOS gene.
To accomplish this, we used 2 distinct murine models of transgenic overexpression, a cardiomyocyte-specific eNOS overexpresser (CS eNOS-Tg) under the control of the alpha-myosin heavy chain promoter, and a systemic eNOS transgenic mouse (SYS eNOS-Tg) under control of the native eNOS promoter with an upstream endothelial enhancer element. Mice were subjected to 30 or 45 minutes of left coronary artery ischemia and 24 or 72 hours of reperfusion. CS eNOS-Tg mice displayed significantly decreased infarct size beyond that of mice with systemic overexpression. Additionally, CS eNOS-Tg mice exhibited better preservation of cardiac function compared with SYS eNOS-Tg mice after myocardial infarction.
These results provide evidence that site-specific targeting of eNOS gene therapy may be more advantageous in limiting MI-R injury and subsequent cardiac dysfunction.
一氧化氮合酶-3（eNOS）衍生的一氧化氮在限制心肌缺血再灌注（MI-R）损伤中的保护作用已得到充分证实。我们之前报道过，eNOS的全身基因过表达可减轻MI-R损伤。本研究的目的是探讨人eNOS基因的组织特异性基因过表达。
为实现这一目标，我们使用了两种不同的转基因过表达小鼠模型，一种是在α-肌球蛋白重链启动子控制下的心肌细胞特异性eNOS过表达小鼠（CS eNOS-Tg），另一种是在天然eNOS启动子及上游内皮增强子元件控制下的全身eNOS转基因小鼠（SYS eNOS-Tg）。对小鼠进行30或45分钟的左冠状动脉缺血及24或72小时的再灌注。与全身过表达的小鼠相比，CS eNOS-Tg小鼠的梗死面积显著减小。此外，心肌梗死后，与SYS eNOS-Tg小鼠相比，CS eNOS-Tg小鼠的心脏功能保存得更好。
这些结果表明，eNOS基因治疗的位点特异性靶向在限制MI-R损伤及随后的心脏功能障碍方面可能更具优势。
