The involvement of matrix metalloproteinases 2 and 9 in rat retinal ischemia |
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Authors: | Nurit Mathalone Nitza Lahat Michal A Rahat Keren Bahar-Shany Yoram Oron Orna Geyer |
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Institution: | (1) Department of Ophthalmology, Carmel Medical Center, 7 Michal Street, Haifa, 34362, Israel;(2) Immunology Research Unit, Carmel Medical Center, Haifa, Israel;(3) The Technion, Israel Institute of Technology, Haifa, Israel;(4) Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;(5) Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel |
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Abstract: | Background The involvement of matrix metalloproteinases (MMPs) in ischemic tissue damage and remodeling has been reported by many investigators.
Our study was designed to investigate the involvement of MMPs and of tissue inhibitors of metalloproteinases (TIMPs) in rat
retinal ischemic injury, the effect of nitric oxide synthase (NOS) inhibitors on MMPs’ activity in this model and whether
minocycline (an MMP inhibitor) is protective in retinal ischemia.
Methods Ninety-four rats were used in the study. Ischemia was induced by 90 min elevation of intraocular pressure. MMPs’ activities
and the effect of NOS inhibitors aminoguanidine (AG) or N-nitro-L-arginine (NNA)] and minocycline on MMPs’ activities were assessed by zymography and TIMPs expression by Western analysis.
Morphological damage was quantified by morphometry of hematoxylin and eosin-stained retinal sections.
Results Retinal extracts exhibited activities of proMMP-9 and proMMP-2. The activity of proMMP-9 increased immediately post ischemia
(PI) and peaked to 4.6 times that of normal untreated controls in ischemic retinas and to 2.6 times that of controls in retinas
of fellow sham-treated eyes at 24 h PI. The relative amount of TIMP-1 increased to 1.9-fold following ischemia and 2.5-fold
in fellow sham-treated eyes at 24 h PI. ProMMP-2 activity increased more than two-fold immediately, at 24 h and at 48 h PI
in ischemic retinas, and insignificantly in fellow sham-treated eyes. Treatment with 25 mg/kg AG or NNA caused a non-significant
increase in proMMP-9 activity at 24 h PI (3.7- and 2.9-fold, respectively, p>0.6). There was no effect of AG or NNA on the activity of proMMP-2. Minocycline significantly attenuated the retinal ischemic
damage, primarily by partially preserving ganglion cells and the inner plexiform layer. Minocyline (0.5 mg/ml or 5 mg/ml)
inhibited MMPs’ activities in ischemic retinal extracts in vitro.
Conclusions MMPs participated in morphological ischemic damage to rat retina. Treatment with minocycline dramatically attenuated damage
to the retina. |
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Keywords: | Ischemia Retina MMPs |
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