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(Investigative Ophthalmology and Visual Science. 2007;48:5699-5707.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0340
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Photoreceptor Protection against Light Damage by AAV-Mediated Overexpression of Heme Oxygenase-1

Ming-Hui Sun,1,2 Jong-Hwei Su Pang,2 Show-Li Chen,3 Ping-Chang Kuo,3 Kuan-Jen Chen,1 Ling-Yuh Kao,1 Ju-Yun Wu,4 Ken-Kuo Lin,1 and Yeou-Ping Tsao4,5,6

1From the Department of Ophthalmology and the 2Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; the 3Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan; the 4Departments of Medical Research and 5Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan; and the 6Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.

PURPOSE. To investigate whether overexpression of the cytoprotective gene heme oxygenase-1 (HO-1) in photoreceptors by gene delivery attenuates cellular injury caused by intense light damage and to document the possible mechanisms of protection.

METHODS. Recombinant adeno-associated virus type 5 (rAAV5) expressing the mouse HO-1 gene (mHO-1) was delivered to cyclic-light reared Sprague-Dawley (SD) rats by subretinal injection. Three weeks after transfer of HO-1 gene, animals were subjected to 2-hour intense light exposure then were returned to darkness. Expression of HO-1, p53, p38, and cellular FLICE inhibitory protein (c-FLIP) at different times after intense light damage was evaluated by Western blot analysis. HO-1 transgene expression, along with expression of c-fos and bcl-2, was analyzed by immunohistochemistry. In addition, the protective effects of HO-1 were evaluated by determining the morphology of the retina. Finally, apoptosis in photoreceptors was measured using TdT-dUTP terminal nick-end labeling (TUNEL) 24 hours after photic injury.

RESULTS. Exogenous administration of HO-1 by gene transfer led to HO-1 transgene expression in photoreceptors. Protection of retina by HO-1 overexpression is evident from the partially preserved retina structure and attenuated apoptosis in photoreceptors after photic injury. Concurrently, overexpression of HO-1 was associated with a decrease in the expression of c-fos and p53, an increase in the activation of p38 and bcl-2, and preserved the expression of c-FLIP.

CONCLUSIONS. Overexpression of HO-1 in photoreceptors protected themselves from subsequent cellular damage caused by intense light exposure. The anti-apoptotic mechanisms of HO-1 may be related to the induction of p38, bcl-2, and c-FLIP and to the suppression of c-fos and p53.






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