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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/H3317    most recent 00700.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Lim, H. K. Articles by Berkowitz, D. E. Search for Related Content PubMed PubMed Citation Articles by Lim, H. K. Articles by Berkowitz, D. E.

Mitochondrial arginase II constrains endothelial NOS-3 activity

Departments of ¹Anesthesiology and Critical Care Medicine, ²Medicine, and ³Biomedical Engineering, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and ⁴Institute of Life Long Health and Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea

Submitted 15 June 2007 ; accepted in final form 3 September 2007

Emerging evidence supports the idea that arginase, expressed in the vascular endothelial cells of humans and other species, modulates endothelial nitric oxide (NO) synthase-3 (NOS-3) activity by regulating intracellular L-arginine bioavailability. Arginase II is thought to be expressed in the mitochondria of a variety of nonendothelial cells, whereas arginase I is known to be confined to the cytosol of hepatic and other cells. The isoforms 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 NO production. Western blot analysis, immunocytochemistry with MitoTracker, and immunoelectron 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 knockout (ArgII^–/–) mice compared with 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 N^G-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^–/– compared with WT mice. 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 regulates NO production, vascular endothelial function, and vascular stiffness by modulating NOS-3 activity.

mitochondria; nitric oxide; vascular stiffness

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