Transgenic Mice Expressing Human Arginase II Gene in Endothelium: Useful for Studying Atherosclerosis and Other Vasculopathies


Cardiovascular disorders associated with endothelial dysfunction, like atherosclerosis, have decreased endothelial nitric oxide (NO) bioavailability. L-arginine, the primary substrate for endothelial nitric oxide synthase (eNOS), is important in the regulation of NO production. Arginase competes with eNOS for L-arginine and has been implicated in the endothelial dysfunction. NIH investigators have generated transgenic mice with human ArgII (hArgII) gene under control of endothelial-specific Tie2 promoter. In these mice, hArgII was expressed at very high levels in all tissues except liver. Analysis has shown that expression of hArgII was endothelium-specific. 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. Level of arginase activity in peritoneal macrophages isolated from the transgenic mice also was also unchanged. However, ArgII overexpression induced signs of endothelial dysfunction. In apoE-knockout mice hArgII led to 2-fold increasing in aortic area with atherosclerotic lesions. The Tie2hArgII transgenic mouse can be useful as a new model for investigating the role of ArgII in endothelial function and development of atherosclerosis.

Potential Commercial Applications: Competitive Advantages:
  • Useful to study the role of arginase II gene in endothelium.
  • Useful for testing the drugs for treatment of the endothelial dysfunction related to eNOS insufficiency, including hypertension.
  • Useful to study mechanisms of atherosclerosis.
 Better model system to study functional significance of arginase II.


Development Stage:
  • Early-stage
  • Pre-clinical
  • In vivo data available (animal)


Inventors:

Boris Vaisman (NHLBI)  ➽ more inventions...

Alan Remaley (NHLBI)  ➽ more inventions...


Intellectual Property:
Research Tool — Patent protection is not being pursued for this technology.

Publications:
Vaisman BL, et al. Abstract 3636: The Effects of Arginase II Overexpression on Endothelial Function in Transgenic Mouse Model. Circulation. 2008 Oct 28;118:S_455.

Licensing Contact:
Michael Shmilovich, J.D.
Email: shmilovm@mail.nih.gov
Phone: 301-435-5019

OTT Reference No: E-255-2010-0
Updated: Aug 30, 2011