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Abstract TP232: Post-stroke Suppression Of Matrix Metalloproteinase-12 Attenuates The Expression Of M1 And M2 Markers And Prevents The Elevation Of Other Matrix Metalloproteinases


 Introduction:
 We previously reported a marked elevation of matrix metalloproteinases (MMP-1, MMP-7, MMP-8, MMP-9, MMP-11, MMP-12, and MMP-14) in the ischemic brain on day 3 after ischemic stroke in a rodent model. Also, we showed that MMP-12 suppression after ischemic stroke attenuates blood-brain barrier (BBB) disruption. The aim of the present study was to examine the effects of MMP-12 suppression on the expression of elevated M1 and M2 microglia/macrophage phenotypes and other MMPs in the ischemic brain. We hypothesized that MMP-12 suppression, by attenuating infiltrating leucocytes (especially monocytes), would decrease the expression of both M1 and M2 markers as well as other MMPs, since activated monocytes are the primary source of elevated MMPs in the ischemic brain.
 
 
 Methods:
 Young adult male Sprague-Dawley rats (n=6/group) were subjected to 2-h transient middle cerebral artery occlusion and received either MMP-12 shRNA (M12sh) expressing plasmids (1 mg/kg, i.v.; formulated as nanoparticles) within 30 min of reperfusion or no treatment. M12sh-treated and untreated ischemia-induced rats along with sham surgery rats were euthanized on day 3 after ischemia and brain tissues were collected for quantitative real-time PCR analysis of specific M1/M2 markers and various MMPs.
 
 
 Results:
 In untreated ischemia-induced animals, the expression of both M1 markers (CD16, CD68, IL-1β, IL-6, and TNFα) and M2 markers (CD163, CD206, Arg1, TGFβ, and IL-10) was increased approximately 10-150 fold over sham operated animals. Similarly, the expression of all MMPs studied (MMP-1, MMP-7, MMP-8, MMP-9, MMP-11, and MMP-14) was elevated approximately 10-30 fold in untreated ischemia-induced animals. M12sh treatment reduced the expression of most M1/M2 markers, notably CD68, IL-10, Arg1, and TGFβ, compared to no treatment. M12sh treatment also strongly reduced the elevated levels of MMP-7, MMP-9, MMP-11, and MMP-14.
 
 
 Conclusions:
 Suppression of MMP-12 leads to a general downregulation of M1/M2 markers and MMPs in the ischemic brain. We attribute these effects to reduced monocyte infiltration and subsequent inflammation. Suppression of MMP-12 could prove to be a promising therapy for ischemic stroke.
