Antiangiogenic mechanisms of simvastatin in retinal endothelial cells.

BACKGROUND: While statins have an anti-angiogenic property, their underlying mechanisms are not fully understood. We investigated intracellular mechanisms of simvastatin-mediated reduction in VEGF-induced signalings. METHODS: The effects of simvastatin on cell proliferation and viability were evaluated by [(3)H]-thymidine incorporation in retinal endothelial cells (RECs) and cell counting. The impact of simvastatin on VEGF-induced phosphorylation of p44/42 mitogen-activated protein (MAP) kinase, myosin light chain (MLC), and VEGF-receptor (VEGFR) 2 were examined by Western blotting. Involvement of the mevalonate pathway in VEGF-induced signaling was also examined. RESULTS: Simvastatin (1 and 10 microM) suppressed VEGF-induced RECs proliferation in a concentration-dependent manner, without affecting cell viability. Simvastatin significantly inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream mediators, p44/42 MAP kinase and MLC. Mevalonate completely reversed VEGF-induced VEGFR2 phosphorylation, but only partially reversed the phosphorylation of p44/42 MAP kinase and MLC. CONCLUSION: These data indicate that simvastatin exerts its anti-angiogenic effects through the reduction of VEGFR2 phosphorylation in RECs at least in part. However, there seems to be both mevalonate-dependent and independent pathway in simvastatin's anti-angiogenic property.

Deterioration of glaucoma after carotid endarterectomy.

A 64-year-old man with a long history of untreated diabetes mellitus had suffered from visual disturbance in his right eye. Neovascular glaucoma in the right eye and diabetic retinopathy in both eyes were found, and ischemic ocular syndrome was suspected for the right eye. Neuroimaging revealed severe stenosis of the right internal carotid artery. He was first treated for diabetes and glaucoma, and then, after these conditions were stabilized, right carotid endarterectomy (CEA) was carried out. Although the operation was uneventful, he suffered from headache and his right sight was blurred on the day after surgery. Right intraocular pressure was markedly increased, and corneal edema and increased iris neovascularization were also recognized. Intensive ophthalmologic care was carried out, but his right vision worsened and was eventually lost. Ocular ischemia causes not only neovascularization of the iris, which leads to insufficient resorption of the aqueous humor, but also insufficient production of the aqueous humor. After CEA, production of the humor is immediately activated, but the resorption capacity does not change, which results in an extraordinary increase in intraocular pressure. Neurosurgeons should be aware that CEA not only improves or avoids worsening of vision in patients with ischemic oculopathy, but can also rarely cause paradoxical devastating visual deterioration.

Role of tumour necrosis factor-α (TNFα) in the functional properties of hyalocytes.

BACKGROUND/AIM: Tumour necrosis factor-α (TNFα) is an inflammatory cytokine that is upregulated in various vitreoretinal diseases including uveitis and diabetic retinopathy. Recently, our studies have indicated that hyalocytes contribute to the pathogenesis of these diseases. However, the impact of TNFα on the functional properties of hyalocytes is unknown. METHODS: Hyalocytes were isolated from bovine eyes. Cellular proliferation, migration and gel contraction in response to TNFα and the other inflammatory cytokines were analysed by thymidine uptake, Boyden's chamber assay and collagen gel contraction assay, respectively. Furthermore, we estimated the effect of dexamethasone on these properties of hyalocytes. RESULTS: TNFα promoted proliferation, migration and gel contraction by hyalocytes. Dexamethasone inhibited TNFα-induced proliferation but not migration. Dexamethasone did not inhibit TNFα-induced gel contraction but further increased contraction. Furthermore, dexamethasone inhibited TNFα-induced extracellular signal-related kinase (ERK)1/2 phosphorylation in hyalocytes. CONCLUSION: This study indicates that TNFα in vitreous and retina causes activation of hyalocytes, and the activated hyalocytes contribute to the pathogenesis of inflammatory vitreoretinal diseases. Steroid treatment appears to inhibit the activation of hyalocytes in the early stages of the diseases, but might have adverse effects in the late stage through membrane contraction.