Abstract 1420: Mitochondrial Arginase II Constrains Endothelial NOS Activity
Background: Arginase II is known as a major isoenzyme in the vascular endothelial cells of humans and other species and modulates endothelial nitric oxide synthase (eNOS) activity by regulating intracellular L-arginine bioavailability. We tested under hypothesis that subcellular localization of arginase II is confined to the mitochondria and mitochondrial arginase II deficiency reciprocally regulates the vascular endothelial NO production, contributes to improve endothelial dysfunction and decrease vascular stiffness.
Methods and Results: Western blot, immunocytochem with Mitotracker and immunoEM confirmed that arginase II is confined predominantly but not exclusively to the mitochondria. Arginase activity was significantly reduced, whereas NO production was significantly increased in aorta and isolated endothelial cells from arginase II knock out (ArgII−/−) compared to WT mice. Vasorelaxation to acetylcholine (ACh) was markedly enhanced and vasoconstriction to phenylephrine (PE) was impaired in ArgII−/− rings. Furthermore inhibition of eNOS by NG -nitro-L-arginine methyl ester (L-NAME) impaired ACh response and restored PE response. The baseline pulse wave velocity was significantly decreased in ArgII−/− mice (3.30 ± 0.21 vs. 3.64 ± 0.12 m/s, ArgII−/− vs. WT, *p<0.01), while 14 days of L-NAME treatment resulted in significant increase the PWV in both WT (4.23 ± 0.11 m/s, **p<0.001) and ArgII−/− mice (4.36 ± 0.20 m/s, **p<0.001).
Conclusions: These data suggest that arginase II is predominantly confined to the mitochondria and this mitochondrial arginase II regulate the NO production, vascular endothelial function, and vascular stiffness by modulating eNOS activity.