on December 27, 2005
Published online before print December 27, 2005, doi: 10.1161/01.HYP.0000198543.34502.d7
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Submitted on July 5, 2005
From the Departments of Anesthesiology and Critical Care Medicine (S.R., D.L., J.S., D.W., D.N., D.E.B.), Medicine (H.C.C., J.M.H.), and Biomedical Engineering (A.R.W., A.A.S., J.M.H., D.E.B.), The Johns Hopkins Medical Institutions, Baltimore, Md. * To whom correspondence should be addressed. E-mail: dberkowi{at}bme.jhu.edu.
Abstract--Arginase, expressed in endothelial cells and upregulated in aging blood vessels, competes with NO synthase (NOS) for L-arginine, thus modulating vasoreactivity and attenuating NO signaling. Moreover, arginase inhibition restores endothelial NOS signaling and L-arginine responsiveness in old rat aorta. The arginase isoform responsible for modulating NOS, however, remains unknown. Because isoform-specific arginase inhibitors are unavailable, we used an antisense (AS) oligonucleotide approach to knockdown arginase I (Arg I). Western blot and quantitative PCR confirmed that Arg I is the predominant isoform expressed in endothelialized aortic rings and is upregulated in old rats compared with young. Aortic rings from 22-month-old rats were incubated for 24 hours with sense (S), AS oligonucleotides, or medium alone (C). Immunohistochemistry, immunoblotting, and enzyme assay confirmed a significant knockdown of Arg I protein and arginase activity in AS but not S or C rings. Conversely, calcium-dependent NOS activity and vascular metabolites of NO was increased in AS versus S or C rings. Acetylcholine (endothelial-dependent) vasorelaxant responses were enhanced in AS versus S or C treated rings. In addition, 1H-oxadiazolo quinoxalin-1-one (10 µmol/L), a soluble guanylyl cyclase inhibitor, increased the phenylephrine response in AS compared with S and C rings suggesting increased NO bioavailability. Finally, L-arginine (0.1 mmol/L)-induced relaxation was increased in AS versus C rings. These data support our hypothesis that Arg I plays a critical role in the pathobiology of age-related endothelial dysfunction. AS oligonucleotides may, therefore, represent a novel therapeutic strategy against age-related vascular endothelial dysfunction.
Revised on July 26, 2005
Knockdown of Arginase I Restores NO Signaling in the Vasculature of Old Rats
Anthony R. White;
Key words: atherosclerosis • nitric oxide • endothelium • aging
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