Use Of Animal Models To Study Genes That Modulate Atherosclerosis

内皮细胞功能障碍导致一氧化氮(NO)的产生减少被认为是许多类型心血管疾病发生的关键因素。血管内皮细胞中的L-精氨酸通过酶合酶(ENOS)产生NO。在内皮细胞中发现的另一种酶-精氨酸酶可能会与eNOS竞争精氨酸，这可能会导致NO产生减少。精氨酸酶以精氨酸酶I和精氨酸酶II两种亚型存在，但目前还没有确定哪种亚型可以降低内皮细胞中NO的水平，以及具体的生理后果是什么。为了研究这一问题，在内皮特异性Tie2启动子的控制下，产生了高表达人精氨酸酶I(HArgI)或人精氨酸酶II(HArgII)基因的转基因小鼠。两种转基因小鼠的内皮细胞中的精氨酸酶活性都升高了，而巨噬细胞中的表达没有明显增加。HArg I或II的过度表达不会导致血浆L-精氨酸水平的显著变化，也不会导致血管活性氧的变化。然而，使用主动脉环研究发现，Tie2hArgII而不是Tie2hArgI小鼠对乙酰胆碱的扩张器反应减弱。此外，当Tie2hArgII小鼠与apoE基因敲除小鼠杂交时，与仅apoE基因敲除小鼠相比，它们在正常饮食下的主动脉粥样硬化显著增加。总之，这些结果表明，抑制hArgII的治疗策略可能有助于预防内皮功能障碍和动脉粥样硬化。

Endothelial cell dysfunction leading to decreased nitric oxide (NO) production is thought to be a key factor in the development of many types of cardiovascular disease. NO is produced from L-arginine in endothelial cells by the enzyme synthase (eNOS). Arginase, another enzyme found in endothelial cells, may compete with eNOS for arginine, which would be predicted to lead to decreased NO production. Arginase exists in two isoforms, arginase I and II, but it has not been definitively established which isoform may lower NO levels in endothelial cells and what the exact physiologic consequences would be. In order to examine this issue, transgenic mice over expressing either human arginase I (hArgI) or II (hArgII) gene under the control of endothelial-specific Tie2 promoter were produced. Both strains of transgenic mice had elevated arginase activity in endothelial cells, with no increased expression evident in macrophages. Over expression of hArg I or II did not lead to significant changes in plasma L-arginine levels or changes in vascular reactive oxygen species. Using aortic ring studies, Tie2hArgII, but not Tie2hArgI mice were found to have, however, diminished dilator response to acetylcholine. Furthermore, when Tie2hArgII mice were crossed with apoE knockout mice, they had a marked increase in aortic atherosclerosis on a normal chow diet compared to just apoE knockout mice. Collectively, these results suggest that therapeutic strategies involving the inhibition of hArgII may be useful for preventing endothelial dysfunction and atherosclerosis.