MicroRNA-222调控血红素氧合酶1在糖尿病视网膜新生血管病变EPCs靶向募集和血管重塑中的保护作用研究

Diabetic retinopathy ( DR) is a progressive neurodegenerative disease that eventually leads to legal blindness. Despite researchers have identified multiple pathogenic mechanisms in DR, the treatment methods of this disease are limited. The pathologic processes, including retinal hypoxia, inflammation and angiogenesis, interact with each other and result in irreversible cellular damage in retinal neurons. As a result, the hypoxia-inflammatory-vascular cross-talk has attracted increasing attention. Our research has indicated the critical importance of miR-222 and its connection with novel protective enzyme Heme Oxygenase-1 (HO-1) in mediating anti-hypoxia,anti-inflammatory, and anti-proliferative effects. The overexpression of HO-1 regulated by miR-222 may achieve functional vascular remodeling represent a novel strategy for therapeutic intervention in the future. In this study, to investigate the effect of miR-222 in angiogenesis induced by DR and the endothelial progenitor cell (EPCs) recruitment to retinal neovascularization sites, we establish STZ-induced diabetic mice model, together with oxygen-induced neovascular retinopathy model (OIR) and in vitro culture of vascular endothelial cells. Further demonstrate the potential effect of miR-222 and HO-1 in functional vascular remodeling and their future therapeutic strategies.

糖尿病视网膜病变机制和治疗是目前研究难点。疾病发展与视网膜缺氧、炎性损伤和血管重塑相关，三者交替并存最终导致不可逆的视觉损害。病变进展过程中，研究抗缺氧、抗炎性损伤关键靶点与功能化血管重塑之间的相互关系和对话机制，有助于深入了解病变机制，干预该过程可维持视网膜结构和功能平衡。申请人前期研究筛选出miR-222作为关键靶点，推测miR-222和经典保护酶HO-1的对话关系既可以减轻视网膜炎性损伤，亦能抑制畸形新生血管生成，引导血管向功能化方向重塑，最终改善整个视网膜的缺氧状态。在此推论下，本课题采用STZ诱导糖尿病视网膜病变小鼠模型、缺氧诱导的视网膜新生血管小鼠模型和体外培养的视网膜血管内皮细胞作为研究对象，以外周血EPCs的定向募集为切入点，研究miR-222调控视网膜HO-1表达变化在抗炎、抗血管生成等方面的作用，进一步阐明其与功能化血管重塑的关系及可能的作用机制。

糖尿病视网膜病变机制和治疗是目前研究难点。疾病发展与视网膜缺氧、炎性损伤和血管重塑相关，三者交替并存最终导致不可逆的视觉损害。病变进展过程中，研究抗缺氧、抗炎性损伤关键靶点与功能化血管重塑之间的相互关系和对话机制，有助于深入了解病变机制，干预该过程可维持视网膜结构和功能平衡。本课题组前期研究筛选出miR-222作为关键靶点，推测miR-222和经典保护酶HO-1的对话关系既可以减轻视网膜炎性损伤，亦能抑制畸形新生血管生成，引导血管向功能化方向重塑，最终改善整个视网膜的缺氧状态。在此推论下，本课题采用STZ诱导糖尿病视网膜病变小鼠模型、缺氧诱导的视网膜新生血管小鼠模型和体外培养的Muller细胞和视网膜血管内皮细胞作为研究对象，研究结果显示mir-222的增强可以抑制HO-1的表达，上调HIF-1a和VEGF表达量。但是抑制mir-222的表达并不能激活HO-1的保护作用。提示mir-222并非HO-1的理想上游调控靶点，但HO-1在糖尿病视网膜病变中的保护作用和血管功能化重塑作用仍有待进一步探索。