Vitamin C prevents zidovudine-induced NAD(P)H oxidase activation and hypertension in the rat.
OBJECTIVE
Cardiovascular risk is increased among HIV-infected patients receiving antiretroviral therapy due to the development of hypertension and metabolic abnormalities. In this study, we investigated the effects of long-term treatment with zidovudine (AZT) and vitamin C, alone and in combination, on blood pressure and on the chain of events linking oxidative stress to cardiac damage in the rat.


METHODS
Six adult Wistar Kyoto rats received AZT (1 mg/ml) in the drinking water for 8 months, six vitamin C (10 g/kg of food) and AZT, six vitamin C alone, and six served as controls.


RESULTS
AZT increased systolic blood pressure, expression of gp91(phox) and p47(phox) subunits of NAD(P)H oxidase, and protein kinase C (PKC) delta activation and reduced antioxidant power of plasma and cardiac homogenates. AZT also caused morphological alterations in cardiac myocyte mitochondria, indicative of functional damage. All of these effects were prevented by vitamin C.


CONCLUSIONS
Chronic AZT administration increases blood pressure and promotes cardiovascular damage through a NAD(P)H oxidase-dependent mechanism that involves PKC delta. Vitamin C antagonizes these adverse effects of AZT in the cardiovascular system.
Papparella
Italia
I
Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, I-35128 Padua, Italy.
Ceolotto
Giulio
G
Berto
Laura
L
Cavalli
Maurizio
M
Bova
Sergio
S
Cargnelli
Gabriella
G
Ruga
Ezia
E
Milanesi
Ornella
O
Franco
Lorenzo
L
Mazzoni
Martina
M
Petrelli
Lucia
L
Nussdorfer
Gastone G
GG
Semplicini
Andrea
A
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000032:analysis / Q000378:metabolism*; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D014815:Vitamins / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology*
D000963:Antimetabolites; D000975:Antioxidants; D008562:Membrane Glycoproteins; C498751:Nsfl1c protein, rat; D009687:Nuclear Proteins; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D014815:Vitamins; D015215:Zidovudine; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D011493:Protein Kinase C; D001205:Ascorbic Acid