Abstract 3636: The Effects of Arginase II Overexpression on Endothelial Function in Transgenic Mouse Model
Endothelium is a major regulator of local vascular homeostasis. Its normal function is crucial for prevention of the development of atherosclerosis, hypertension and other cardiovascular disorders. Reduced nitric oxide (NO) bioavailability is one of the earliest and most important markers of endothelial dysfunction. L-arginine is the substrate for nitric oxide synthases (NOS). Arginase (Arg) can compete with eNOS for L-arginine and thus may play a role in endothelial dysfunction. To further investigate the role of ArgII in endothelial function and in atherosclerosis we generated transgenic mice with human ArgII (hArgII) gene under control of endothelial-specific Tie2 promoter. Expression of hArgII was measured by RT-PCR in eight tissues of transgenic males and compared with the level of mouse ArgII (mArgII) expression in kidneys of normal C57Bl mice, which was taken as 100%. hArgII was expressed at very high levels in all tissues, especially in aorta (2700%), heart (3500%), kidney (1600%), lung (9860%) and muscle (2000%). Arginase activity was elevated 4.6 – 62 fold in all tissues except liver. Lung endothelial cells isolated from hArgII transgenic mice had 4.4-fold greater of arginase activity than whole lung. Resident peritoneal macrophages from hArgII transgenic and normal mice had similar levels of arginase activity, confirming endothelial specificity of the Tie2 promoter. Overexpression of hArgII neither led to significant changes in plasma level of arginine, citrulline, NOHA, ADMA, SDMA and ornithine, nor to changes in plasma lipid levels. However, ArgII overexpression on apoE-knockout background was accompanied by a 10% increase in plasma total cholesterol (p<0.05). hArgII transgenic mice also had blood pressure (mean arterial and diastolic) that averaged 17% higher than controls. Aortic ring segments from hArgII transgenic mice, precontracted with phenylephrine (10−6M), exhibited decreased endothelium-dependent relaxation to increasing concentrations of acetylcholine (10−9 to 10−3.5M), indicating endothelial dysfunction secondary to NO insufficiency. These results show that the Tie2hArgII transgenic mouse is a new model for investigating the role of ArgII in endothelial function and in atherosclerosis.