Exp Mol Med.  2012 Oct;44(10):594-602.

Increased arginase II activity contributes to endothelial dysfunction through endothelial nitric oxide synthase uncoupling in aged mice

• Shin W
• Berkowitz
• Ryoo S

Abstract

The incidence of cardiovascular disease is predicted to increase as the population ages. There is accumulating evidence that arginase upregulation is associated with impaired endothelial function. Here, we demonstrate that arginase II (ArgII) is upregulated in aortic vessels of aged mice and contributes to decreased nitric oxide (NO) generation and increased reactive oxygen species (ROS) production via endothelial nitric oxide synthase (eNOS) uncoupling. Inhibiting ArgII with small interfering RNA technique restored eNOS coupling to that observed in young mice and increased NO generation and decreased ROS production. Furthermore, enhanced vasoconstrictor responses to U46619 and attenuated vasorelaxation responses to acetylcholine in aged vasculature were markedly improved following siRNA treatment against ArgII. These results might be associated with increased L-arginine bioavailability. Collectively, these results suggest that ArgII may be a valuable target in age-dependent vascular diseases.

Keyword

aging; arginase II; endothelial nitric oxide synthase uncoupling; small interfering RNA; vascular diseases

MeSH Terms

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology
Aging
Animals
Aorta/enzymology/physiopathology
Arginase/genetics/*metabolism
Endothelium, Vascular/*enzymology/physiopathology
Enzyme Induction
Gene Knockdown Techniques
Mice
Mice, Inbred C57BL
Nitric Oxide/metabolism
Nitric Oxide Synthase Type III/*metabolism
RNA, Small Interfering/genetics
Reactive Oxygen Species/metabolism
Up-Regulation
Vasoconstriction/drug effects