Liegl Raffael, Koenig Susanna, Siedlecki Jakob, Haritoglou Christos, Kampik Anselm, Kernt Marcus
Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany.
PLoS One. 2014 Feb 26;9(2):e88203. doi: 10.1371/journal.pone.0088203. eCollection 2014.
Due to their high prevalence, retinal vascular diseases including age related macular degeneration (AMD), retinal vein occlusions (RVO), diabetic retinopathy (DR) and diabetic macular edema have been major therapeutic targets over the last years. The pathogenesis of these diseases is complex and yet not fully understood. However, increased proliferation, migration and angiogenesis are characteristic cellular features in almost every retinal vascular disease. The introduction of vascular endothelial growth factor (VEGF) binding intravitreal treatment strategies has led to great advances in the therapy of these diseases. While the predominant part of affected patients benefits from the specific binding of VEGF by administering an anti-VEGF antibody into the vitreous cavity, a small number of non-responders exist and alternative or additional therapeutic strategies should therefore be evaluated. The mammalian target of rapamycin (mTOR) is a central signaling pathway that eventually triggers up-regulation of cellular proliferation, migration and survival and has been identified to play a key role in angiogenesis. In the present study we were able to show that both retinal pigment epithelial (RPE) cells as wells as human umbilical vein endothelial cells (HUVEC) are inhibited in proliferating and migrating after treatment with temsirolimus in non-toxic concentrations. Previous studies suggest that the production of VEGF, platelet derived growth factor (PDGF) and other important cytokines is not only triggered by hypoxia but also by mTOR itself. Our results indicate that temsirolimus decreases VEGF and PDGF expression on RNA and protein levels significantly. We therefore believe that the mTOR inhibitor temsirolimus might be a promising drug in the future and it seems worthwhile to evaluate complementary therapeutic effects with anti-VEGF drugs for patients not profiting from mono anti-VEGF therapy alone.
由于其高患病率，包括年龄相关性黄斑变性（AMD）、视网膜静脉阻塞（RVO）、糖尿病性视网膜病变（DR）和糖尿病性黄斑水肿在内的视网膜血管疾病在过去几年一直是主要的治疗靶点。这些疾病的发病机制复杂，尚未完全了解。然而，增殖、迁移和血管生成增加是几乎每种视网膜血管疾病的特征性细胞特征。血管内皮生长因子（VEGF）结合玻璃体内治疗策略的引入在这些疾病的治疗方面取得了巨大进展。虽然大多数受影响的患者通过向玻璃体腔注射抗VEGF抗体来特异性结合VEGF而受益，但仍有少数无反应者存在，因此应评估替代或额外的治疗策略。雷帕霉素的哺乳动物靶点（mTOR）是一条核心信号通路，最终触发细胞增殖、迁移和存活的上调，并已被确定在血管生成中起关键作用。在本研究中，我们能够证明，在用无毒浓度的替西罗莫司治疗后，视网膜色素上皮（RPE）细胞和人脐静脉内皮细胞（HUVEC）的增殖和迁移均受到抑制。先前的研究表明，VEGF、血小板衍生生长因子（PDGF）和其他重要细胞因子的产生不仅由缺氧触发，也由mTOR本身触发。我们的结果表明，替西罗莫司在RNA和蛋白质水平上显著降低VEGF和PDGF的表达。因此，我们认为mTOR抑制剂替西罗莫司可能是未来一种有前景的药物，对于那些不能从单一抗VEGF治疗中获益的患者，评估其与抗VEGF药物的互补治疗效果似乎是值得的。
