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Glutathione Articles - HIV
Vascular oxidative stress and nitric oxide depletion in
HIV-1 transgenic rats are reversed by glutathione restoration
Erik R. Kline, Dean J. Kleinhenz, Bill Liang, Sergey Dikalov, David M.
Guidot, C. Michael Hart, Dean P. Jones, and Roy L. Sutliff
Am J Physiol Heart Circ Physiol. 2008 June ; 294(6): H2792–H2804
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ABSTRACT
Human immunodeficiency virus
(HIV)-infected patients have a higher incidence of oxidative stress,
endothelial dysfunction, and cardiovascular disease than uninfected
individuals. Recent reports have demonstrated that viral proteins
upregulate reactive oxygen species, which may contribute to elevated
cardiovascular risk in HIV-1 patients. In this study we employed an
HIV-1 transgenic rat model to investigate the physiological effects of
viral protein expression on the vasculature. Markers of oxidative stress
in wild-type and HIV-1 transgenic rats were measured using electron spin
resonance,
fluorescence microscopy, and various molecular techniques. Relaxation
studies were completed on isolated aortic rings, and mRNA and protein
were collected to measure changes in expression of nitric oxide (NO) and
superoxide sources. HIV-1 transgenic rats displayed significantly less
NO hemoglobin,
serum nitrite, serum S-nitrosothiols, aortic tissue NO, and impaired
endothelium dependent vasorelaxation than wild-type rats. NO reduction
was not attributed to differences in endothelial NO synthase (eNOS)
protein expression, eNOS-Ser1177 phosphorylation, or tetrahydrobiopterin
availability. Aortas from HIV-1 transgenic rats had higher levels of
superoxide and 3-nitrotyrosine but did not differ in expression of
superoxide-generating sources NADPH oxidase
or xanthine oxidase. However, transgenic aortas displayed decreased
superoxide dismutase and glutathione. Administering the glutathione
precursor procysteine decreased superoxide, restored aortic NO levels
and NO-hemoglobin, and improved endothelium-dependent relaxation in
HIV-1 transgenic rats. These results show that HIV-1 protein expression
decreases NO and causes endothelial dysfunction. Diminished antioxidant
capacity increases vascular superoxide levels, which reduce NO
bioavailability and promote peroxynitrite generation. Restoring
glutathione levels reverses HIV-1 protein-mediated effects on
superoxide, NO, and vasorelaxation.
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