Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, 02114, United States.
Department of Pathology, Boston University School of Medicine, Boston, MA, 02118, United States.
Sci Rep. 2017 May 24;7(1):2329. doi: 10.1038/s41598-017-02407-7.
Phagocytosis of daily shed photoreceptor outer segments is an important function of the retinal pigment epithelium (RPE) and it is essential for retinal homeostasis. RPE dysfunction, especially impairment of its phagocytic ability, plays an essential role in the pathogenesis of age-related macular degeneration (AMD). Statins, or HMG CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, are drugs with multiple properties that have been extensively used to treat hyperlipidemia. However, their effect on RPE cells has not been fully elucidated. Here we report that high dose atorvastatin increased the phagocytic function of ARPE-19 cells, as well as rescue the cells from the phagocytic dysfunction induced by cholesterol crystals and oxidized low-density lipoproteins (ox-LDL), potentially by increasing the cellular membrane fluidity. Similar effects were observed when evaluating two other hydrophobic statins, lovastatin and simvastatin. Furthermore, atorvastatin was able to block the induction of interleukins IL-6 and IL-8 triggered by pathologic stimuli relevant to AMD, such as cholesterol crystals and ox-LDL. Our study shows that statins, a well-tolerated class of drugs with rare serious adverse effects, help preserve the phagocytic function of the RPE while also exhibiting anti-inflammatory properties. Both characteristics make statins a potential effective medication for the prevention and treatment of AMD.
每日脱落的光感受器外节被视网膜色素上皮（RPE）吞噬，这是一个重要的功能，它对于维持视网膜内环境稳定至关重要。RPE 功能障碍，尤其是吞噬能力的损伤，在年龄相关性黄斑变性（AMD）的发病机制中起着重要作用。他汀类药物，或 HMG CoA（3-羟基-3-甲基戊二酰辅酶 A）还原酶抑制剂，是具有多种特性的药物，已广泛用于治疗高脂血症。然而，它们对 RPE 细胞的影响尚未完全阐明。在这里，我们报告阿托伐他汀的高剂量增加了 ARPE-19 细胞的吞噬功能，并能挽救胆固醇晶体和氧化型低密度脂蛋白（ox-LDL）诱导的吞噬功能障碍，这可能是通过增加细胞膜流动性实现的。当评估另外两种疏水性他汀类药物洛伐他汀和辛伐他汀时，也观察到了类似的效果。此外，阿托伐他汀能够阻断与 AMD 相关的病理刺激物（如胆固醇晶体和 ox-LDL）诱导的白细胞介素 IL-6 和 IL-8 的产生。我们的研究表明，他汀类药物是一类耐受性良好的药物，副作用罕见且严重，有助于保持 RPE 的吞噬功能，同时具有抗炎特性。这两个特性使他汀类药物成为预防和治疗 AMD 的一种潜在有效药物。
