当前位置: X-MOL 学术Diabetes › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis
Diabetes ( IF 6.2 ) Pub Date : 2020-01-08 , DOI: 10.2337/db19-0713
Wenyi Wu 1, 2 , Guohong Zhou 2, 3 , Haote Han 2 , Xionggao Huang 2, 4 , Heng Jiang 2, 5 , Shizuo Mukai 6 , Andrius Kazlauskas 7 , Jing Cui 8 , Joanne Aiko Matsubara 8 , Bart Vanhaesebroeck 9 , Xiaobo Xia 1 , Jiantao Wang 10 , Hetian Lei 11
Affiliation  

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform δ is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

中文翻译:


PI3Kδ 作为病理性血管生成的新型治疗靶点



糖尿病视网膜病变是糖尿病最常见的微血管并发症,在晚期糖尿病视网膜病变中会出现由多种细胞组成的玻璃体纤维血管膜,其中包括血管内皮细胞(EC)。迫切需要针对这种糖尿病并发症的新治疗方法。在这里,我们报道在培养的人视网膜微血管内皮细胞中,高葡萄糖诱导p110δ的表达,该蛋白也在糖尿病患者的纤维血管膜的内皮细胞中表达。已知受体调节的 PI3K 同工型 δ 的催化亚基在白细胞中高度富集。通过遗传和药理学方法,我们发现培养的 EC 中的 p110δ 活性控制血管内皮生长因子、碱性成纤维细胞生长因子和表皮生长因子诱导的 Akt 激活、细胞增殖、迁移和管形成。使用氧诱导视网膜病变的小鼠模型,发现 p110δ 失活可减弱病理性视网膜血管生成。 p110δ 抑制剂已被批准用于人类 B 细胞恶性肿瘤。我们的数据表明,拮抗 p110δ 为糖尿病视网膜病变提供了一个以前未被重视的治疗机会。
更新日期:2020-01-08
down
wechat
bug