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Yuki Morizane, Kimio Takeuchi, Jun Suzuki, Takeru Yoshimura, Yusuke Murakami, Maki Kayama, Fumiaki Kumase, Benoit Viollet, Joan Miller, Demetrios Vavvas; AMP-activated Protein Kinase Suppresses Matrix Metalloproteinase-9 Expression and Cell Migration of Mouse Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2016.
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© ARVO (1962-2015); The Authors (2016-present)
Increased degradation of extracellular matrix by matrix metalloproteinases (MMPs) and aberrant migration of retinal pigment epithelium (RPE) are the important pathologic features of proliferative vitreoretinopathy (PVR). Recently, we reported that AMPK, a central regulator of energy homeostasis, suppresses MMP-9 expression in mouse embryonic fibroblasts (JBC 2011). In this study, we investigated the effect of AMPK activation on MMP-9 expression and cell migration of RPE.
We used primary RPEs isolated from AMPKα wild type (WT), AMPKα1 or α2 subunit single-knockout (AMPKα1-/- and AMPKα2-/-, respectively) mouse. RPEs were treated with TGFβ-2 with or without AMPK activator, 5-amino-4-imidazole carboxamide riboside (AICAR). The effects of AICAR on TGFβ-2 induced MMP-9 expression and cell migration were determined by zymography, ELISA, quantitative real time RT-PCR and chemoinvasion assay. The involvement of protein kinases such as ERK, JNK, p38 MAPK, and smad2/3 was investigated by western blotting.
TGFβ-2 increased MMP-9 expression dose dependently and facilitated RPE migration. AMPK activation with AICAR significantly inhibited these TGFβ-2-elicited effects, whereas AICAR inhibitor (5-iodotubericidin, IODO) recovered them. In AMPKα1-/- RPE, the increasing rate of MMP-9 expression after TGFβ-2 stimulation was higher than that of WT RPE. In contrast, in AMPKα2-/- RPE, the increasing rate of MMP-9 expression was lower than WT RPE. Treatment with both TGFβ-2 and AICAR activated JNK pathway and pretreatment with IODO suppressed the JNK pathway. Consistently, the selective JNK inhibitor (SP600125) significantly and dose-dependently attenuated the inhibitory effect of AICAR on the TGFβ-2 induced MMP-9 expression.
Activation of AMPK suppresses TGFβ-2 induced MMP-9 expression and cell migration. The suppressive effect of AMPK activation may depend on AMPKα1 subunit rather than α2 subunit. These results suggest that AMPK can be a therapeutic target to inhibit aberrant RPE migration in PVR.
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