The contribution of various NOS gene products to HIV-1 coat protein (gp120)-mediated retinal ganglion cell injury.
OBJECTIVE
There is growing evidence that the neuronal pathology seen with HIV-1 is mediated, at least in part, through an excitotoxic/free radical pathway. Nitric oxide (NO) plays a critical role in the nervous system, in both normal and pathologic states, and appears to be involved in a variety of excitotoxic pathways. Whether isoforms of nitric oxide synthase (NOS) are involved in gp120-mediated neuronal loss in the retina was therefore explored.


METHODS
To determine which (if any) of the various isoforms of NOS are critical in gp120-mediated damage in the retina, neuronal NOS-deficient [nNOS(-/-)], endothelial NOS-deficient [eNOS(-/ -)], and immunologic NOS-deficient [iNOS(-/-)] mice were subjected to intravitreal injections of gp120.


RESULTS
Retinal ganglion cells in the nNOS(-/-) mouse were relatively resistant to gp120, manifesting attenuation of gp120-induced injury compared with wild-type mice. The iNOS(-/-) and eNOS(-/-) mice were as susceptible to gp120 toxicity as control animals. NOS inhibitors were protective against this toxicity.


CONCLUSIONS
The presence of nNOS is a prerequisite for the full expression of gp120-mediated loss in the retina; eNOS and iNOS do not appear to play a significant role.
Dreyer
E B
EB
Department of Ophthalmology, Scheie Eye Institute, Philadelphia Veterans Administration, University of Pennsylvania, USA.
Zurakowski
D
D
Gorla
M
M
Vorwerk
C K
CK
Lipton
S A
SA
D000818:Animals; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology
D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse