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1 ACCM, JHMI, Baltimore, Maryland, United States
2 ACCM, Jhmi, Baltimore, Maryland, United States
3 Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: dberkow1{at}jhmi.edu.
Emerging evidence supports the idea that arginase expressed in the vascular endothelial cells of humans and other species, modulates endothelial nitric oxide synthase (NOS-3) activity by regulating intracellular L-arginine bioavailability. Arginase II is thought to be confined to be expressed in the mitochondria of a variety of non-endothelial cells while arginase I is known to confined to the cytosol of hepatic and other cells. The isoform/s that regulate NOS-3 and their subcellular distribution however remain incompletely characterized. We therefore tested the hypothesis that arginase II is confined to the mitochondria and that mitochondrial arginase II reciprocally regulates vascular endothelial nitric oxide (NO) production. Western blots, immunocytochemistry with MitoTracker and immuno-electron-microscopy confirmed that arginase II is confined predominantly but not exclusively to the mitochondria. Arginase activity was significantly decreased, whereas NO production was significantly increased in the aorta and isolated endothelial cells from arginase II knock out (ArgII-/-) mice compared to wild type (WT) mice. The vasorelaxation response to acetylcholine (ACh) was markedly enhanced and the vasoconstrictor response to phenylephrine (PE) attenuated in ArgII-/- in pressurized mouse carotid arteries. Furthermore, inhibition of NOS-3 by NG-nitro-L-arginine methyl ester (L-NAME) impaired ACh response and restored the PE response to that observed in WT vessels. Vascular stiffness, as assessed by pulse wave velocity (PWV) was significantly decreased in ArgII-/- mice compared to WT. On the other hand 14 days of oral L-NAME treatment significantly increased PWV in both WT and ArgII-/- mice such that they were not significantly different from one another. These data suggest that arginase II is predominantly confined to the mitochondria and that this mitochondrial arginase II regulate NO production, vascular endothelial function, and vascular stiffness by modulating NOS-3 activity.
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